Cancers, Volume 15, Issue 13 (July-1 2023) – 270 articles

Distal humeral replacement (DHR) is a limb-salvage option for the endoprosthetic reconstruction of bone defects following the resection of a primary bone sarcoma. As primary bone sarcomas are only occasionally located around the distal humerus, there is a paucity of information regarding postoperative function, and patients’ resumption of sporting activities. With advances in diagnostics and in surgical and oncological treatment leading to an increased patient life expectancy and higher quality of life, patients’ functional outcome and return to sports activities are of increasing interest. Between 1997 and 2021, a total of 24 patients underwent DHR with a single-design modular implant at a tertiary sarcoma center. A total of 14 patients who died of their disease were excluded, leaving a study cohort of 10 patients, with a median age of 30 years on the day of surgery (IQR 20–37). At the last follow-up, after a median of 230 months (IQR 165–262), the median MSTS was 19 (IQR 13–24), the median TESS was 79 (IQR 66–87), the median SEV was 38% (IQR 24–53), the median TS was 6 (IQR 4–7), and the median WAS was 3 (IQR 1–8). Among the variables of gender, surgery on the dominant extremity, intraoperative nerve resection, extra-articular tumor resection, chemotherapy, radiotherapy, and revision surgeries, none were associated with a better/lower functional outcome score or return to sports activities. However, a higher level of sports performance prior to diagnosis (WAS > 10) was associated with a higher level of sports performance postoperatively (p = 0.044). Full article

Background: Previous studies reported mitochondrial and endoplasmic reticulum redox stress in peripheral blood mononucleated cells (PBMCs) of treatment-naïve Hodgkin lymphoma (HL) patients. Here, we assessed whether this response also applies to non-HL (NHL) patients, and whether the oxidative damage is a selective feature of PBMCs or, rather, also affects tissues not directly involved in the inflammatory response. Methods: Isolated PBMCs of 28 HL, 9 diffuse large B cell lymphoma, 8 less aggressive-NHL, and 45 controls underwent flow cytometry to evaluate redox stress and uptake of the glucose analogue 2-NBDG. This analysis was complemented with the assay of malondialdehyde (MDA) levels and enzymatic activity of glucose-6P-dehydrogenase and hexose-6P-dehydrogenase (H6PD). In all lymphoma patients, ¹⁸F-fluoro-deoxyglucose uptake was estimated in the myocardium and skeletal muscles. Results: Mitochondrial reactive oxygen species generation and MDA levels were increased only in HL patients as well as H6PD activity and 2-NBDG uptake. Similarly, myocardial FDG retention was higher in HL than in other groups as opposed to a similar tracer uptake in the skeletal muscle. Conclusions: Redox stress of PBMCs is more pronounced in HL with respect to both NHL groups. This phenomenon is coherent with an increased activity of H6PD that also extends to the myocardium. Full article

Background: Liquid biopsies are revolutionary tools used to detect tumor-specific genetic alterations in body fluids, including the use of cell-free DNA (cfDNA) for molecular diagnosis in cancer patients. In brain tumors, cerebrospinal fluid (CSF) cfDNA might be more informative than plasma cfDNA. Here, we assess the use of CSF cfDNA in pediatric embryonal brain tumors (EBT) for molecular diagnosis. Methods: The CSF cfDNA of pediatric patients with medulloblastoma (n = 18), ATRT (n = 3), ETMR (n = 1), CNS NB FOXR2 (n = 2) and pediatric EBT NOS (n = 1) (mean cfDNA concentration 48 ng/mL; range 4–442 ng/mL) and matched tumor genomic DNA were sequenced by WES and/or a targeted sequencing approach to determine single-nucleotide variations (SNVs) and copy number alterations (CNA). A specific capture covering transcription start sites (TSS) of genes of interest was also used for nucleosome footprinting in CSF cfDNA. Results: 15/25 CSF cfDNA samples yielded informative results, with informative CNA and SNVs in 11 and 15 cases, respectively. For cases with paired tumor and CSF cfDNA WES (n = 15), a mean of 83 (range 1–160) shared SNVs were observed, including SNVs in classical medulloblastoma genes such as SMO and KMT2D. Interestingly, tumor-specific SNVs (mean 18; range 1–62) or CSF-specific SNVs (mean 5; range 0–25) were also observed, suggesting clonal heterogeneity. The TSS panel resulted in differential coverage profiles across all 112 studied genes in 7 cases, indicating distinct promoter accessibility. Conclusion: CSF cfDNA sequencing yielded informative results in 60% (15/25) of all cases, with informative results in 83% (15/18) of all cases analyzed by WES. These results pave the way for the implementation of these novel approaches for molecular diagnosis and minimal residual disease monitoring. Full article

Background: Sarcomas are rare, aggressive cancers which frequently metastasise to the lungs. Following diagnosis, patients typically undergo staging by means of a CT scan of their chest. This often identifies indeterminate pulmonary nodules (IPNs), but the significance of these in high-grade soft tissue sarcoma (STS) is unclear. Identifying whether these are benign or malignant is important for clinical decision making. This study analyses the clinical relevance of IPNs in high-grade STS. Methods: All patients treated at our centre for high-grade soft tissue sarcoma between 2010 and 2020 were identified from a prospective database. CT scans and their reports were reviewed, and survival data were collected from patient records. Results: 389 suitable patients were identified; 34.4% had IPNs on their CT staging scan and 20.1% progressed into lung metastases. Progression was more likely with IPNs ≥ 5 mm in diameter (p = 0.006), multiple IPNs (p = 0.013) or bilateral IPNs (p = 0.022), as well as in patients with primaries ≥ 5 cm (p = 0.014), grade 3 primaries (p = 0.009) or primaries arising deep to the fascia (p = 0.041). The median time to progression was 143 days. IPNs at diagnosis were associated with an increased risk of developing lung metastases and decreased OS in patients with grade 3 STS (p = 0.0019 and p = 0.0016, respectively); this was not observed in grade 2 patients. Conclusions: IPNs at diagnosis are associated with significantly worse OS in patients with grade 3 STS. It is crucial to consider the primary tumour as well as the IPNs when considering the risk of progression. Surveillance CT scans should be carried out within 6 months. Full article

Lung cancer is one of the most common cancers worldwide, and despite improvements in treatment regimens, patient prognosis remains poor. Lung adenocarcinomas develop from the lung epithelia and understanding how specific genetic and environmental factors lead to oncogenic transformation in these cells is of great importance to define the pathways that contribute to tumorigenesis. The recent rise in the use of immunotherapy to treat different cancers has prompted the exploration of immune modulators in tumour cells that may provide new targets to manipulate this process. Of these, the B7 family of cell surface receptors, which includes PD-1, is of particular interest due to its role in modulating immune cell responses within the tumour microenvironment. B7-H3 (CD276) is one family member that is upregulated in many cancer types and suggested to contribute to tumour–immune interactions. However, the function and ligand(s) for this receptor in normal lung epithelia and the mechanisms through which the overexpression of B7-H3 regulate cancer progression in the absence of immune cell interactions remain unclear. Here, we present evidence that B7-H3 is associated with one of the key rate-limiting metabolic enzymes IMPDH2, and the localisation of this complex is altered in human lung cancer cells that express high levels of B7-H3. Mechanistically, the IMPDH2:B7-H3 complex provides a protective role in cancer cells to escape oxidative stress triggered by chemotherapy, thus leading to cell survival. We further demonstrate that the loss of B7-H3 in cancer cells has no effect on growth or migration in 2D but promotes the expansion of 3D spheroids in an IMPDH2-dependent manner. These findings provide new insights into the B7-H3 function in the metabolic homeostasis of normal and transformed lung cancer cells, and whilst this molecule remains an interesting target for immunotherapy, these findings caution against the use of anti-B7-H3 therapies in certain clinical settings. Full article

(1) Background: Autologous, allogeneic hematopoietic cell transplantation (HCT) and other cellular therapies, including CAR T cell and gene therapy, constitute a cornerstone in the management of various benign and malignant hematological disorders. Invasive fungal infections (IFD) remain a significant cause of morbidity and mortality in HCT recipients. Therefore, we investigated the prevalence and risk factors of IFD following HCT and other cellular therapies in an era of novel antifungal prophylaxis. (2) Methods: In this study, we retrospectively enrolled adult HCT recipients who were treated at our JACIE-accredited center according to standard operating procedures over the last decade (2013–2022). (3) Results: 950 patients who received cellular therapies were studied. None of the 19 CAR T cell and neither of the two gene therapy recipients developed IFD whereas 3/456 autologous HCT recipients who suffered from primary refractory/relapsed lymphomas presented with probable IFD. Overall, 11 patients who received allogeneic HCT experienced probable IFD, possible IFD was found in 31/473, and IFD was proven in 10/473. A second IFD episode was present in three patients. Four-year OS was significantly lower in proven compared to probable IFD (p = 0.041) and was independently associated with HCT-CI (p = 0.040) and chronic GVHD (p = 0.045). (4) Conclusions: In this real-world cohort, the prevalence of proven and probable IFD in an era of novel antifungal prophylaxis was found to be relatively low. However, IFDs were associated with poor outcomes for patients who received allogeneic HCT. Full article

Background: The detection of the EGFR T790M (T790M) mutation in non-small cell lung cancer (NSCLC) patients who progressed under treatment with first- or second-generation EGFR-tyrosine kinase inhibitors (TKIs) is important to offer a subsequent therapy with a third-generation EGFR-TKI. Liquid biopsy is a powerful tool to determine the T790M mutation status. Several liquid biopsy platforms with varying degrees of accuracy are available to test for T790M mutations, and sensitivities may differ among these methods. Methods: As no standard exists for the testing of T790M mutation in liquid biopsy, we performed a collaborative study to describe and compare the sensitivity of different in-house liquid biopsy platforms for the detection of the T790M mutation, EGFR exon 19 deletion (del19) and EGFR L858R mutation (L858R) across multiple participating laboratories in seven Central and Eastern European countries. Results: Of the 25 invited laboratories across Central and Eastern Europe, 21 centers participated and received 10 plasma samples spiked with cell-line DNA containing the T790M, del19, or L858R mutation in different concentrations. In-house PCR-based and NGS-based methods were used accordingly, and results were reported as in routine clinical practice. Two laboratories, which used the AmoyDx^® EGFR 29 Mutations Detection Kit (AmoyDx) with Cobas^® cfDNA Sample Preparation Kit and QX200 Droplet Digital PCR (ddPCR) with the QIAamp Circulating Nucleic Acid Kit identified all ten samples correctly. Cobas^® EGFR Mutation Test v2 (Cobas), the NGS methods, and the Idylla^TM detection method used in this study performed within the known sensitivity range of each detection method. Conclusions: If a negative result was obtained from methods with lower sensitivity (e.g., Cobas), repeated liquid biopsy testing and/or tissue biopsy analysis should be performed whenever possible, to identify T790M-positive patients to allow them to receive the optimal second-line treatment with a third-generation EGFR TKI. Full article

Background: Non-overlapping somatic mutations in BRAF, NRAS, or NF1 genes occur in 85% of metastatic melanoma patients. It is not known whether these mutations affect immunotherapy outcome. Materials and methods: Next-Gen sequencing of 324 oncogenes was performed in 73 metastatic melanoma patients. A retrospective review of immunotherapy outcome was performed. Results: BRAF fusions/internal rearrangements, BRAF V600E, NRAS, NF1 mutations, and triple-negative genotypes occurred in 6.9%, 30.1%, 17.8%, 32.9%, and 12.3% of patients, respectively. Median potential follow-up was 41.0 months. Patients with BRAF fusion/rearrangement had decreased progression-free and overall survival (p = 0.015). The other genotypes each had similar progression-free and overall survival. Patients who achieved a complete best objective response at 12 months (n = 36, 49.3%) were found to have significantly improved survival compared those who failed to achieve remissions (n = 37, 50.7%, p < 0.001). Conclusions: The most important determinant of long-term survival was achievement of a complete response by 12 months following immunotherapy. PR and SD were not a stable type of response and generally resulted in progression and death from melanoma. Rare patients with BRAF fusions or rearrangements had decreased progression-free and overall survival following initial immunotherapy. Other BRAF, NRAS, or NF1 mutations were not associated with significant differences in outcome. Full article

Historically, the role of radiation in gynecological metastatic disease involved palliation for pain or bleeding. Stereotactic Body Radiation Therapy (SBRT) has shown survival benefits in oligometastatic disease from varying primary histologies in recent randomized trials. However, gynecologic primary oligometastases have been underrepresented in these trials. Recent studies across gynecological malignancy types have similarly shown favorable outcomes and acceptable toxicities from treating recurrent or oligometastatic gynecologic cancer (ROMGC) patients with definitive radiation therapy. The largest body of literature reported on the use of SBRT in ovarian cancer, which was found to be an effective option, especially in the setting of chemo-resistant disease. Despite the encouraging outcomes using SBRT in oligometastatic gynecologic malignancies, SBRT remains underutilized given the lack of randomized studies studying ROMGC with long term follow-up. While waiting for future prospective trials to establish the role of SBRT as the standard of care in ROMGC patients, this review focuses on reporting the advantages and drawbacks of this technique and examines the current literature to help guide patient centered treatment decisions. Full article

Glioblastoma IDH wildtype is the most frequent brain tumor in adults. It shows a highly malignant behavior and devastating outcomes. To date, there is still no targeted therapy available; thus, patients’ median survival is limited to 12–15 months. Epithelial growth factor receptor (EGFR) is an interesting targetable candidate in advanced precision medicine for brain tumor patients. In this study, we performed integrated epigenome-wide DNA-methylation profiling of 866,895 methylation specific sites in 50 glioblastoma IDH wildtype samples, comparing EGFR amplified and non-amplified glioblastomas. We found 9849 significantly differentially methylated CpGs (DMCGs) with Δβ ≥ 0.1 and p-value < 0.05 in EGFR amplified, compared to EGFR non-amplified glioblastomas. Of these DMCGs, 2380 were annotated with tiling (2090), promoter (117), gene (69) and CpG islands (104); 7460 are located at other loci. Interestingly, the list of differentially methylated genes allocated eleven functionally relevant RNAs: five miRNAs (miR1180, miR1255B1, miR126, miR128-2, miR3125), two long non-coding RNAs (LINC00474, LINC01091), and four antisense RNAs (EPN2-AS1, MNX1-AS2, NKX2-2-AS1, WWTR1-AS1). Gene ontology (GO) analysis showed enrichment of “DNA replication-dependent nucleosome assembly”, “chromatin silencing at rDNA”, “regulation of gene silencing by miRNA”, “DNA packaging”, “posttranscriptional gene silencing”, “gene silencing by RNA”, “negative regulation of gene expression, epigenetic”, “regulation of gene silencing”, “protein-DNA complex subunit organization”, and “DNA replication-independent nucleosome organization” pathways being hypomethylated in EGFR amplified glioblastomas. In summary, dissecting the methylomes of EGFR amplified and non-amplified glioblastomas revealed altered DNA replication, DNA packaging, chromatin silencing and gene silencing pathways, opening potential novel targets for future precision medicine. Full article

Despite aggressive treatment, glioblastoma has a poor prognosis due to its infiltrative nature. Spectroscopic MRI-measured brain metabolites, particularly the choline to N-acetylaspartate ratio (Cho/NAA), better characterizes the extent of tumor infiltration. In a previous pilot trial (NCT03137888), brain regions with Cho/NAA ≥ 2x normal were treated with high-dose radiation for newly diagnosed glioblastoma patients. This report is a secondary analysis of that trial where spectroscopic MRI-based biomarkers are evaluated for how they correlate with progression-free and overall survival (PFS/OS). Subgroups were created within the cohort based on pre-radiation treatment (pre-RT) median cutoff volumes of residual enhancement (2.1 cc) and metabolically abnormal volumes used for treatment (19.2 cc). We generated Kaplan–Meier PFS/OS curves and compared these curves via the log-rank test between subgroups. For the subgroups stratified by metabolic abnormality, statistically significant differences were observed for PFS (p = 0.019) and OS (p = 0.020). Stratification by residual enhancement did not lead to observable differences in the OS (p = 0.373) or PFS (p = 0.286) curves. This retrospective analysis shows that patients with lower post-surgical Cho/NAA volumes had significantly superior survival outcomes, while residual enhancement, which guides high-dose radiation in standard treatment, had little significance in PFS/OS. This suggests that the infiltrating, non-enhancing component of glioblastoma is an important factor in patient outcomes and should be treated accordingly. Full article

CDSSs are being continuously developed and integrated into routine clinical practice as they assist clinicians and radiologists in dealing with an enormous amount of medical data, reduce clinical errors, and improve diagnostic capabilities. They assist detection, classification, and grading of brain tumours as well as alert physicians of treatment change plans. The aim of this systematic review is to identify various CDSSs that are used in brain tumour diagnosis and prognosis and rely on data captured by any imaging modality. Based on the 2020 preferred reporting items for systematic reviews and meta-analyses (PRISMA) protocol, the literature search was conducted in PubMed and Engineering Village Compendex databases. Different types of CDSSs identified through this review include Curiam BT, FASMA, MIROR, HealthAgents, and INTERPRET, among others. This review also examines various CDSS tool types, system features, techniques, accuracy, and outcomes, to provide the latest evidence available in the field of neuro-oncology. An overview of such CDSSs used to support clinical decision-making in the management and treatment of brain tumours, along with their benefits, challenges, and future perspectives has been provided. Although a CDSS improves diagnostic capabilities and healthcare delivery, there is lack of specific evidence to support these claims. The absence of empirical data slows down both user acceptance and evaluation of the actual impact of CDSS on brain tumour management. Instead of emphasizing the advantages of implementing CDSS, it is important to address its potential drawbacks and ethical implications. By doing so, it can promote the responsible use of CDSS and facilitate its faster adoption in clinical settings. Full article

Endometrial cancer (EC) is a major gynecological malignancy with rising morbidity and mortality worldwide. The aim of this study was to explore a safe and readily available sample and a sensitive and effective detection method and its biomarkers for early diagnosis of EC, which is critical for patient prognosis. This study designed a panel targeting variants for EC-related genes, assessed its technical performance by comparing it with whole-exon sequencing, and explored the diagnostic potential of endometrial biopsies using the Pipelle aspirator, cervical samples using the Pap brush, and vaginal specimens using the swab from 38 EC patients and 208 women with risk factors for EC by applying targeted panel sequencing (TPS). TPS produced high-quality data (Q30 > 85% and mapping ratios > 99.35%) and was found to have strong consistency with whole-exome sequencing (WES) in detecting pathogenic mutations (92.11%), calculating homologous recombination deficiency (HRD) scores (r = 0.65), and assessing the microsatellite instability (MSI) status of EC (100%). The sensitivity of TPS in detection of EC is slightly better than that of WES (86.84% vs. 84.21%). Of the three types of samples detected using TPS, endometrial biopsy using the Pipelle aspirator had the highest sensitivity in detection of pathogenic mutations (81.87%) and the best consistency with surgical tumor specimens in MSI (85.16%). About 84% of EC patients contained pathogenic mutations in PIK3CA, PTEN, TP53, ARID1A, CTNNB1, KRAS, and MTOR, suggesting that this small gene set can achieve an excellent pathogenic mutation detection rate in Chinese EC patients. The custom panel combined with ultra-deep sequencing serves as a sensitive method for detecting genetic lesions from endometrial biopsy using the Pipelle aspirator. Full article

Breast lesions of uncertain malignant potential (B3) are frequently diagnosed in the era of breast cancer (BC) screening and their management is controversial. They are generally removed surgically, but some international organizations and guidelines for breast research suggest follow-up care alone or, more recently, propose vacuum-assisted excision (VAE). The risk of upgrade to BC is known, but very little data exist on its role as risk factor for future BC development. We analyzed 966 B3 lesions diagnosed at our institution, 731 of which had long-term follow-up available. Surgical removal was performed in 91%, VAE in 3.8%, and follow-up in 5.2% of cases. The B3 lesions included flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), lobular intraepithelial neoplasia (LIN), atypical papillary lesions (PLs), radial scars (RSs), and others. Overall, immediate upgrade to BC (invasive or in situ) was 22.7%. After long-term follow-up, 9.2% of the patients were diagnosed with BC in the same or contralateral breast. The highest risk was associated with ADH diagnosis, with 39.8% of patients upgraded and 13.6% with a future BC diagnosis (p < 0.0001). These data support the idea that B3 lesions should be removed and provide evidence to suggest annual screening mammography for women after a B3 diagnosis because their BC risk is considerably increased. Full article

Background: There is limited data on the optimal time interval between the last dose of neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) in high-grade serous ovarian carcinoma (HGSC). Methods: We retrospectively identified patients with stage IIIC/IV HGSC who received NACT followed by IDS during a 15-year period (January 2003–December 2018) in our Institution. Results: Overall, 115 patients with stage IIIC/IV HGSC were included. The median age of diagnosis was 62.7 years (IQR: 14.0). A total of 76.5% (88/115) of patients were diagnosed with IIIC HGSC and 23.5% (27/115) with IV HGSC. Median PFS was 15.7 months (95% CI: 13.0–18.5), and median OS was 44.7 months (95% CI: 38.8–50.5). Patients were categorized in groups according to the time interval from NACT to IDS: <4 weeks (group A); 4–5 weeks (group B); 5–6 weeks (group C); >6 weeks (group D). Patients with a time interval IDS to NACT ≥4 weeks had significantly shorter PFS (p = 0.004) and OS (p = 0.002). Median PFS was 26.6 months (95% CI: 24–29.2) for patients undergoing IDS <4 weeks after NACT vs. 14.4 months (95% CI: 12.6–16.2) for those undergoing IDS later (p = 0.004). Accordingly, median OS was 66.3 months (95% CI: 39.1–93.4) vs. 39.4 months (95% CI: 31.8–47.0) in the <4 week vs. >4 week time interval NACT to IDS groups (p = 0.002). On multivariate analysis, the short time interval (<4 weeks) from NACT to IDS was an independent factor of PFS (p = 0.004) and OS (p = 0.003). Conclusion: We have demonstrated that performing IDS within four weeks after NACT may be associated with better survival outcomes. Multidisciplinary coordination among ovarian cancer patients is required to avoid any unnecessary delays. Full article

An increasing number of observational studies have described an association between aspirin use and a reduced risk of incident hepatocellular carcinoma. We performed this meta-analysis to provide a comprehensive and updated aggregate assessment of the effect of aspirin on HCC incidence. Two independent authors performed a systematic search of the literature, utilising the Medline, Embase, Scopus, and PubMed databases. A total of 16 studies (12 cohort studies, and 4 case-control studies) were selected for inclusion, with a large number of studies excluded, due to an overlapping study population. The pooled analysis of cohort studies involving a total population of approximately 2.5 million subjects, 822,680 aspirin users, and 20,626 HCC cases demonstrated a 30% reduced risk of HCC associated with aspirin use (adjusted HR 0.70, 95%CI 0.60–0.81). There was a similar but non-significant association observed across the case-control studies (adjusted OR 0.60, 95%CI 0.32–1.15, p = 0.13), which involved a total of 1961 HCC cases. In a subgroup meta-analysis of patients with cirrhosis, the relationship between aspirin use and incident HCC diminished to non-significance (adjusted HR 0.96, 95%CI 0.84–1.09). Aspirin use was associated with a statistically significant increase in bleeding events when all relevant studies were pooled together (adjusted HR 1.11, 95%CI 1.02–1.22). Prospectively collected data should be sought, to define the optimal patient group in which aspirin is safe and effective for the chemoprophylaxis of HCC. Full article

Data on the possible connection between circulating adipokines and PanNENs are limited. This novel study aimed to assess the serum levels of leptin and adiponectin and their ratio in patients with PanNENs and to evaluate the possible relationship between them and PanNEN’s grade or stage, including the presence of metastases. The study group consisted of PanNENs (n = 83), and healthy controls (n = 39). Leptin and adiponectin measurement by an ELISA assay was undertaken in the entire cohort. The serum concentration of adiponectin was significantly higher in the control group compared to the study group (p < 0.001). The concentration of leptin and adiponectin was significantly higher in females than in males (p < 0.01). Anincreased leptin–adiponectin ratio was observed in well-differentiated PanNENs (G1) vs. moderatelydifferentiated PanNENs (G2) (p < 0.05). An increased leptin–adiponectin ratio was found in PanNENs with Ki-67 < 3% vs. Ki-67 ≥ 3% (p < 0.05). PanNENs with distal disease presented lower leptin levels (p < 0.001) and a decreased leptin–adiponectin ratio (p < 0.01) compared with the localized disease group. Leptin, adiponectin, and the leptin–adiponectin ratio may serve as potential diagnostic, prognostic, and predictive biomarkers for PanNENs. Leptin levels and the leptin–adiponectin ratio may play an important role as predictors of malignancy and metastasis in PanNENs. Full article

Metastatic castration-resistant prostate cancer (mCRPC) is a progressive stage of prostate cancer that often spreads to the bone. Radium-223, a bone-targeting radiopharmaceutical, has been shown to improve the overall survival in mCRPC in patients without visceral metastasis. However, the impact of prior systemic therapy on the treatment outcome of mCRPC patients receiving radium-223 remains unclear. This study aimed to investigate the optimal choice of systemic therapy before radium-223 in mCRPC patients. The study included 41 mCRPC patients who received radium-223 therapy, with 22 receiving prior enzalutamide and 19 receiving prior abiraterone. The results showed that the median overall survival was significantly longer in the enzalutamide group than in the abiraterone group (25.1 months vs. 14.8 months, p = 0.049). Moreover, the number of patients requiring blood transfusion was higher in the abiraterone group than in the enzalutamide group (9.1% vs. 26.3%, p = 0.16). The study also found that the number of doses of Radium-223 received was significantly associated with overall survival (≥5 vs. <5, HR 0.028, 95%CI 0.003–0.231, p = 0.001). Our study provides insights into the optimal treatment choice for mCRPC prior to radium-223, indicating that enzalutamide prior to radium-223 administration may have better outcomes compared to abiraterone in mCRPC patients without visceral metastasis. Full article

Patients with cancer often experience changes in function during and after treatment but it is not clear what cancer types, and associated clinical factors, affect function. This study evaluated patient-reported functional impairments between specific cancer types and risk factors related to disease status and non-cancer factors. A cross-sectional study evaluating 332 individuals referred to cancer rehabilitation clinics was performed at six U.S. hospitals. The PROMIS Cancer Function Brief 3D Profile was used to assess functional outcomes across the domains of physical function, fatigue, and social participation. Multivariable modeling showed an interaction between cancer type and cancer status on the physical function and social participation scales. Subset analyses in the active cancer group showed an effect by cancer type for physical function (p < 0.001) and social participation (p = 0.008), but no effect was found within the non-active cancer subset analyses. Brain, sarcoma, prostate, and lymphoma were the cancers associated with lower function when disease was active. Premorbid neurologic or musculoskeletal impairments were found to be predictors of lower physical function and social participation in those with non-active cancer; cancer type did not predict low function in patients with no evidence of disease. There was no differential effect of cancer type on fatigue, but increased fatigue was significantly associated with lower age (0.027), increased body mass index (p < 0.001), premorbid musculoskeletal impairment (p < 0.015), and active cancer status (p < 0.001). Anticipatory guidance and education on the common impairments observed with specific cancer types and during specific stages of cancer care may help improve/support patients and their caregivers as they receive impairment-driven cancer rehabilitation care. Full article

Colorectal cancer (CRC) is the second most common cause of cancer-related mortality in the United States. Among newly diagnosed patients with CRC, 20% will present with metastatic disease and another 25% will develop metastases. The surgical resection of the primary tumor and metastatic disease sites confers the best chance at long-term survival. Unfortunately, many patients will recur after resection or present with unresectable disease. As such, metastatic CRC is commonly treated with a combination of surgery, systemic therapy, and/or liver-directed therapies. Despite best efforts, 5-year survival for unresectable metastatic CRC is only about 20%. CRC is a heterogeneous disease and the underlying genetic differences inform behavior, treatment strategy, and prognosis. Given the limitations of cytotoxic chemotherapy and the growing role of molecular profiling, research has focused on identifying and developing targeted therapies. We herein review how genetic profiling informs prognosis, crucial cell-signaling pathways that play a role in CRC carcinogenesis, and currently approved targeted therapies for metastatic CRC. Full article

An accurate estimation of AML prognosis is complex since it depends on patient-related factors, AML manifestations at diagnosis, and disease genetics. Furthermore, the depth of response, evaluated using the level of MRD, has been established as a strong prognostic factor in several AML subgroups. In recent years, this rapidly evolving field has made the prognostic evaluation of AML more challenging. Traditional prognostic factors, established in cohorts of patients treated with standard intensive chemotherapy, are becoming less accurate as new effective therapies are emerging. The widespread availability of next-generation sequencing platforms has improved our knowledge of AML biology and, consequently, the recent ELN 2022 recommendations significantly expanded the role of new gene mutations. However, the impact of rare co-mutational patterns remains to be fully disclosed, and large international consortia such as the HARMONY project will hopefully be instrumental to this aim. Moreover, accumulating evidence suggests that clonal architecture plays a significant prognostic role. The integration of clinical, cytogenetic, and molecular factors is essential, but hierarchical methods are reaching their limit. Thus, innovative approaches are being extensively explored, including those based on “knowledge banks”. Indeed, more robust prognostic estimations can be obtained by matching each patient’s genomic and clinical data with the ones derived from very large cohorts, but further improvements are needed. Full article

Implementation of population-based colorectal cancer screening programs has led to increases in the incidence of pT1 colorectal cancer. These incipient invasive cancers have a very good prognosis and can be treated locally, but more than half of these cases are treated with surgery due to the presence of histological high-risk criteria. These high-risk criteria are suboptimal, with no consensus among clinical guidelines, heterogeneity in definitions and assessment, and poor concordance in evaluation, and recent evidence suggests that some of these criteria considered high risk might not necessarily affect individual prognosis. Current criteria classify most patients as high risk with an indication for additional surgery, but only 2–10.5% have lymph node metastasis, and the residual tumor is present in less than 20%, leading to overtreatment. Patients with pT1 colorectal cancer have excellent disease-free survival, and recent evidence indicates that the type of treatment, whether endoscopic or surgical, does not significantly impact prognosis. As a result, the protective role of surgery is questionable. Moreover, surgery is a more aggressive treatment option, with the potential for higher morbidity and mortality rates. This article presents a comprehensive review of recent evidence on the clinical management of pT1 colorectal cancer. The review analyzes the limitations of histological evaluation, the prognostic implications of histological risk status and the treatment performed, the adverse effects associated with both endoscopic and surgical treatments, and new advances in endoscopic treatment. Full article

Laryngeal cancer is the second most common malignancy of the head and neck, worldwide. Immunotherapy targeting checkpoint inhibitors has been approved for the treatment of patients with recurrent or metastatic laryngeal cancer but has a relatively low response rate and outcomes that leave many patients underserved. Targeting the cGAS–STING signaling pathway can potentially improve the activation of immune effector cells, although its role in the development and progression of laryngeal cancer has not yet been investigated in depth. Fifty-nine tumor samples from patients with pathologically confirmed squamous cell carcinoma of the larynx, stage I–IV non-metastatic disease, who were treated at the University Hospital of Split, were immunohistochemically stained for the expression of STING, cGAS, CD8, CD68, and CD163. Elevated tumor cell-intrinsic STING expression was positively associated with stage IV (p = 0.0031), pT3, and pT4 laryngeal cancers (p = 0.0336) as well as with higher histological grades (G2 and G3) (p = 0.0204) and lymph node-positive tumors (p = 0.0371). After adjusting for age, sex, location, and cGAS expression, elevated STING expression was significantly associated with stage IV cancer in a multiple logistic regression model (β = 1.849, SE = ±0.8643, p = 0.0324). Elevated STING expression represents a potentially favorable predictive biomarker for new therapeutic approaches involving STING agonists combined with immunotherapy and DNA-damaging agents (radiotherapy, cisplatin, and PARP inhibitors) in laryngeal cancer. Full article

Despite a recent overall decrease in colorectal cancer (CRC) incidence and mortality, there has been a significant rise in CRC diagnoses in young adults. Early onset colorectal cancer (EOCRC) is defined as CRC diagnosed before the age of 50. Possible predisposing conditions include not only genetic syndromes but also other risk factors, such as microbiome alteration, antibiotic exposure, obesity, diabetes mellitus, and inflammatory bowel disease. EOCRC tends to be diagnosed later than in the older counterpart because of a lack of awareness and the fact that screening for CRC usually starts at the age of 50. Furthermore, CRC in young adults seems to be related to unique molecular features and more aggressive clinical behavior. This paper aims to provide an in-depth review of this poorly understood subject, with a comprehensive review of the state of the art and considerations for future perspectives. Full article

The burden of hepatocellular carcinoma (HCC) continues to pose a significant global health problem. Several systemic therapies have recently been shown to improve survival for patients with unresectable disease. However, evidence to support the use of neoadjuvant or adjuvant systemic therapies in patients with resectable disease is limited, despite the high risk of recurrence. Neoadjuvant and adjuvant systemic therapies are being investigated for their potential to reduce recurrence after resection and improve overall survival. Our review identified various early-phase clinical trials showing impressive preliminary signals of pathologic complete response in resectable disease, and others suggesting that neoadjuvant therapies—particularly when combined with adjuvant strategies—may convert unresectable disease to resectable disease and cause significant tumor necrosis, potentially decreasing recurrence rates. The role of adjuvant therapies alone may also play a part in the management of these patients, particularly in reducing recurrence rates. Heterogeneity in trial design, therapies used, patient selection, and a scarcity of randomized phase III trials necessitate the cautious implementation of these treatment strategies. Future research is required to identify predictive biomarkers, optimize the timing and type of therapeutic combinations, and minimize treatment-related adverse effects, thereby personalizing and enhancing treatment strategies for patients with resectable and borderline resectable HCC. Full article

Mounting evidence links the phenomenon of enhanced recruitment of tumor-associated macrophages towards cancer bulks to neoplastic growth, invasion, metastasis, immune escape, matrix remodeling, and therapeutic resistance. In the context of cancer progression, naïve macrophages are polarized into M1 or M2 subtypes according to their differentiation status, gene signatures, and functional roles. While the former render proinflammatory and anticancer effects, the latter subpopulation elicits an opposite impact on pancreatic ductal adenocarcinoma. M2 macrophages have gained increasing attention as they are largely responsible for molding an immune-suppressive landscape. Through positive feedback circuits involving a paracrine manner, M2 macrophages can be amplified by and synergized with neighboring neoplastic cells, fibroblasts, endothelial cells, and non-cell autonomous constituents in the microenvironmental niche to promote an advanced disease state. This review delineates the molecular cues expanding M2 populations that subsequently convey notorious clinical outcomes. Future therapeutic regimens shall comprise protocols attempting to abolish environmental niches favoring M2 polarization; weaken cancer growth typically assisted by M2; promote the recruitment of tumoricidal CD8⁺ T lymphocytes and dendritic cells; and boost susceptibility towards gemcitabine as well as other chemotherapeutic agents. Full article

Cancer represents a significant and persistent global health burden, with its impact underscored by its prevalence and devastating consequences. Whereas numerous oncogenes could contribute to cancer development, a group of transcription factors (TFs) are overactive in the majority of tumors. Targeting these TFs may also combat the downstream oncogenes activated by the TFs, making them attractive potential targets for effective antitumor therapeutic strategy. One such TF is yin yang 1 (YY1), which plays crucial roles in the development and progression of various tumors. In preclinical studies, YY1 inhibition has shown efficacy in inhibiting tumor growth, promoting apoptosis, and sensitizing tumor cells to chemotherapy. Recent studies have also revealed the potential of combining YY1 inhibition with immunotherapy for enhanced antitumor effects. However, clinical translation of YY1-targeted therapy still faces challenges in drug specificity and delivery. This review provides an overview of YY1 biology, its role in tumor development and progression, as well as the strategies explored for YY1-targeted therapy, with a focus on their clinical implications, including those using small molecule inhibitors, RNA interference, and gene editing techniques. Finally, we discuss the challenges and current limitations of targeting YY1 and the need for further research in this area. Full article

In children with bladder/prostate (BP) and perianal rhabdomyosarcoma (RMS), we use a hybrid treatment concept for those suitable, combining organ-preserving tumor resection and high-dose rate brachytherapy (HDR-BT). This treatment concept has been shown to improve outcomes. However, it is associated with specific challenges for the clinicians. The exact position of the tubes for BT is a prerequisite for precise radiotherapy. It can finally be determined only with an MRI or CT scan. We evaluated the use of an intraoperative MRI (iMRI) to control the position of the BT tubes and for radiotherapy planning in all patients with BP and perianal RMS who received the above-mentioned combination therapy in our department since January 2021. iMRI was used in 12 children. All tubes were clearly localized. No adverse events occurred. In all 12 children, radiotherapy could be started on time. In a historical cohort without iMRI, this was not possible in 3 out of 20 children. The use of iMRI in children with BP and perianal RMS improved patient safety and treatment quality. This technology has proven to be successful for the patient population we have defined and has become a standard procedure in our institution. Full article