Aim: The aim of the current study was to evaluate the potential clinical impact of clonal evolution detected by fluorescence in situ hybridization (FISH) in untreated chronic lymphocytic leukaemia (CLL) patients managed with a watch-and-wait strategy.
Methods: We performed both overall survival (OS) and time to first treatment (TTFT) analysis. For the first one, we exploited a real-life cohort of 123 consecutive CLL patients followed at our institution, for which at least a second FISH evaluation during watch and wait was available. For TTFT analysis, we considered only patients treated after the second FISH sample (n = 69).
Results: Considering the original cohort, patients who acquired a FISH abnormality displayed a worse outcome with a median OS of 91.9 months compared to 147.3 months for patients who did not acquire any FISH abnormalities (P = 0.007). Unmutated immunoglobulin heavy chain gene (IGHV) genes were associated with a higher probability of acquiring a FISH abnormality (P = 0.04). Turning to TTFT analysis, patients who gained at least one FISH abnormality (n = 7, 10%) were characterised by an earlier treatment requirement with a median TTFT of 1.1 months, compared to 2.7 months in patients who did not acquire any FISH abnormalities
Conclusions: The dynamic acquisition of karyotypic abnormalities by FISH predicts poor outcomes and early treatment requirement in CLL patients. Our results suggest that FISH analysis could be integrated with other clinical and biological features to obtain dynamic scores that are able to predict outcomes at different phases of disease history.
To fully implement precision medicine, a deeper understanding of biomarkers, companion diagnostics, and their use in clinical trials is needed. Here, we describe key events in biomarker discovery and clinical trial design, and how those stages may be streamlined to fast-track approval of companion diagnostics (CDx). We discuss crucial qualities of a successful CDx that include understanding the prevalence of the marker in the intention to treat population, careful consideration of the scoring scheme that will be used in later clinical trial stages, and reliability of the performance of the CDx, in addition to other necessary features.
Mechanical forces play a key role in the initiation and progression of cancer. Intercellular interactions between fibroblasts and cancer cells contribute a large portion of the mechanical forces in tumor tissue. Hence, further investigation of the mechanical force-mediated intercellular interactions between cancer cells and fibroblasts is urgently needed, given the slow progress in the management of various solid cancers. In our previous study, we observed obvious mechanical force-mediated interactions between hepatocellular carcinoma (HCC) cells and fibroblasts through integrins and ECM proteins by using our coculture model and discovered that these interactions play important roles in 3D structure formation and tumor growth, suggesting their potential application in HCC treatment. In this review, we summarize the recent research progress in this field in hopes of providing insight into the development of potential anticancer strategies, with a special focus on HCC.
Hepatocellular carcinoma (HCC) is categorized among the most common primary malignant liver cancer and a primary global cause of death from cancer. HCC tends to affect males 2-4 times more than females in many nations. The main factors that raise the incidence of HCC are chronic liver diseases, hepatotropic viruses like hepatitis B (HBV) and C (HCV), non-alcoholic fatty liver disease, exposure to toxins like aflatoxin, and non-alcoholic steatohepatitis (NASH). Among these, hepatitis B and C are the most prevalent causes of chronic hepatitis globally. Metformin, which is made from a naturally occurring compound called galegine, derived from the plant Galega officinalis (G. officinalis), has been found to exhibit antitumor effects in a wide range of malignancies, including HCC. In fact, compared to patients on sulphonylureas or insulin, studies have demonstrated that metformin treatment significantly lowers the risk of HCC in patients with chronic liver disease. This article will first describe the molecular mechanism of hepatitis B and C viruses in the development of HCC. Then, we will provide detailed explanations about metformin, followed by a discussion of the association between metformin and hepatocellular carcinoma caused by the viruses mentioned above.
P90 Ribosomal S6 Kinases (RSKs) constitute a class of Serine/Threonine (Ser/Thr) protein kinases and play a critical role as downstream targets in the Raf/MEK/ERK signaling pathway. Gaining insight into the biological function of RSK family proteins, given their functions in various tumors, is vital. The RSK family is involved in the regulation of cellular functions including cell proliferation, motility, invasion, and survival. The RSK family comprises four human isoforms (RSK1, RSK2, RSK3, and RSK4). The activation of RSK protein kinases is mediated through direct phosphorylation by extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphoinositide-dependent kinase 1 (PDK1) after the Ras/MAPK (mitogen-activated protein kinase) pathway is activated. Recent evidence suggests that RSK family proteins promote the onset and metastasis of cancer, leading to the association of the protein expression of these kinases with various cancer types, such as colorectal cancer (CRC), breast cancer, lung cancer, kidney cancer, leukemia, esophageal squamous cell carcinoma, ovarian cancer, glioma, and endometrial cancer. In this review, we summarize the latest research on the RSK family, focusing on its role in patients with CRC, along with associated treatment challenges and limitations. This information enhances our comprehension of the regulation and function of RSK family proteins, highlighting their potential as both clinical biomarkers for diagnosing CRC and targets for molecular therapeutic interventions in the future.
Aim: The purpose of this study is to enhance the understanding of bladder cancer and the role of cancer-associated fibroblasts (CAFs) in its progression. We aim to identify CAF-specific biomarkers and develop a prognostic prediction model based on CAFs, thereby contributing to the advancement of treatment strategies and the identification of prognostic and predictive biomarkers for bladder cancer.
Method: We employed single-cell RNA sequencing to detect biomarkers for CAFs in bladder cancer cells. Bladder cancer cohorts were categorized into low- and high-CAF groups using the ssGSEA algorithm. The study also explored the association between CAF-related scores, immune-related cells, and immune checkpoint-related genes. Furthermore, we performed GSVA analysis to understand the biological features of CAFs and their link to various cancer-related pathways.
Result: Ten genes were identified as CAF markers in bladder cancer cells. A significant difference was found with 2712 differentially expressed genes between low-CAF and high-CAF tissues. The CAFs-based prognostic prediction model included nine genes (ALDH1L2, AL450384.2, EMP1, LINC02362, WFIKKN1, GOLGA8A, POU5F1, AL354919.2, PTPRR), which are potentially crucial in predicting bladder cancer prognosis. The GSVA analysis revealed the involvement of several cancer-related pathways, such as WNT, toll-like receptor, TGF-beta, MAPK, and MTOR signaling pathways, in the CAFs-based prognostic model.
Conclusion: This study highlights the significant role of CAFs in the progression and prognosis of bladder cancer. The identified CAF biomarkers and the constructed prognostic model provide valuable insights for future research and potential therapeutic targets. CAF-dependent pathways are promising for the development of new treatments and improving the prognosis of bladder cancer patients.
The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) will continue to rise in the United States over the next several decades. Thus, efforts to reduce treatment intensity, mitigate long-term physical and psychological sequelae of treatment, and simplify surveillance regimens for patients with HPV-related OPSCC are critical. Liquid biomarkers, namely plasma circulating tumor HPV DNA (ctDNA), have shown considerable promise for improvements in these domains by guiding personalized and adaptive treatment de-escalation paradigms and predicting disease recurrence in the survivorship period. Preliminary reports suggest an even broader impact of plasma HPV ctDNA assays for HPV-related OPSCC surveillance beyond the mere detection of cancer recurrence and metastasis. For instance, such assays may reduce the need for costly imaging studies, alleviate the financial toxicities of survivorship care, and improve care access and patient satisfaction. Currently, veterans and underserved populations are disproportionately affected by the financial burden of cancer surveillance and survivorship care. These disparities negatively impact oncologic outcomes, healthcare access, and utilization, specifically among veterans with HPV-related OPSCC. As such, we posit that HPV ctDNA monitoring may be of unique benefit and impact in the surveillance period for these patients specifically. Herein, we provide a narrative review of the current literature supporting the formal clinical evaluation of HPV ctDNA monitoring in veterans with HPV-related OPSCC.
In Italy, a nationwide population-based colorectal cancer (CRC) screening initiative has been in place since 2006. In recent years, there has been a growing interest in involving community pharmacies in this activity. This commentary provides an insightful analysis of the integration between the screening program of the Local Health Authority (LHA) of Bologna (Northern Italy) and community pharmacies. A horizontal integration at the micro level with service and clinical integrations supported by meso-level policy (regional authority) was applied. Four types of integration such as normative, informational, financial and functional serving as enablers were implemented. A high level of depth of consensus, connectivity, communication, and trust was pursued. The program achieved large participation from community pharmacies, with 91.1% (n = 234) of pharmacies in the LHA territory actively participating. On average, each pharmacy served 1,228 (range, 1,021-1,519) target citizens. Between 2021 (the first full year under the community pharmacy model) and 2022, pharmacies delivered an annual mean of 68,295 kits (range, 12-840). In 2021, there was a remarkably high level of screening completion, with 93.7% of fecal immunochemical tests being returned to pharmacies. This percentage increased by 3.3% in 2022. In our setting, pharmacy involvement improved service quality by introducing complete traceability of kits and specimen flow, as well as temperature control. It also led to a 4.6% increase in attendance rates compared to the previous organizational model (61.6% vs. 57%; P < 0.001). Finally, additional European experiences involving community pharmacies in organized CRC screening programs, resembling the Bologna setting, are reported.
Aim: Our study aimed to explore the prognostic predictive potential of a novel RNA-based signature called ImmuneScore in advanced non-squamous NSCLC patients receiving combined immune checkpoint inhibitor (ICI) treatment and chemotherapy.
Methods: RNA-sequencing data of 113 patients screened out from ORIENT-11 trial were retrospectively analyzed. ImmuneScore was calculated by the ESTIMATE algorithm. The association of ImmuneScore with early tumor progression, progression-free survival (PFS), and overall survival (OS) was analyzed using chi-square test, Cox regression test, and log-rank test. Receiver operating characteristic (ROC) curves were generated, with higher values of area under the ROC curves (AUCs) indicating better prediction ability.
Results: ImmuneScore was negatively correlated with early tumor progression rate (4.3% vs. 18.6%, P = 0.013) while positively correlated with PFS (HR = 0.29, 95%CI: 0.16-0.53, P < 0.001) and OS (HR = 0.32,
Conclusion: ImmuneScore serves as a novel RNA-based prognostic signature superior to PD-L1 in advanced non-squamous NSCLC patients receiving chemotherapy combined with ICI therapy. Higher ImmuneScore indicates lower early tumor progression rate, longer PFS, and longer OS.
Colorectal cancer (CRC) is one of the most common malignancies of the digestive tract, with increasing morbidity and mortality worldwide, and is the third most common malignancy in the world. At present, the main treatment methods for CRC include surgery, chemotherapy, targeted therapy, and immunotherapy. Regulation of the gut microbiota is one of the most promising new strategies for CRC treatment. Gut microbiota interacts with host cells to regulate many physiological processes, such as energy acquisition, metabolism, and immune responses. Recent studies have found that a combination of gut microbiota with targeted therapy and immunotherapy could improve the therapeutic effect of colon cancer compared with treatment alone. This article reviews the mechanism of microbiota regulation in CRC and the latest progress of intestinal microbiota in targeted therapy and immunotherapy of CRC, which is helpful in developing potential prevention or treatment strategies for colorectal cancer.
Neutrophils are known as the body's first line of defense against invading pathogens, which are the most abundant bone-marrow-derived innate immune cells accounting for 50%-70% of all white blood cells in human peripheral blood. With in-depth research in recent years, neutrophils have also been recognized as one of the main immune cells in the tumor microenvironment (TME), playing an important role in tumor development. Neutrophils can promote tumor metastasis through secretion of chemokines and cytokines and formation of neutrophil extracellular traps (NETs). Also, neutrophil targeting treatment has shown a promising anticancer effect. In this article, we summarized the recent research progress related to the significant role of neutrophils in tumor metastasis, as well as the current progression and limitations of targeting neutrophils in tumor therapeutics. This review can provide a comprehensive understanding of the role of neutrophils in the TME and the development of a new anticancer strategy.
Cancer immunotherapy utilizes checkpoint inhibitors to amplify the antitumor immune response. The DNA damage repair system plays a crucial role in preserving genome stability, offering therapeutic avenues for tumor treatment by impeding the DNA damage repair pathway. In cancer immunotherapy, checkpoint inhibitors are used to enhance the antitumor immune response. The DNA damage response (DDR) and immune response are inseparably intertwined and have the potential for synergy. Various recent studies have demonstrated that DDR inhibitors (DDRis) can substantially enhance the clinical efficacy of immunotherapy for hepatocellular carcinoma (HCC) by enhancing the immune response of cancer cells. This article primarily describes the immunotherapy of HCC and compiles the research findings and advancements in clinical applications of combined immunotherapy with DDRis. This study provides insight into the application of the DDR pathway in immunotherapy and provides invaluable insights for the clinical advancement of precise and efficacious treatment strategies.
Melatonin (N-acetyl-5 methoxytryptamine) is an indolic compound present in almost all fungi, plants, and animals. This neurohormone is synthesized and secreted into the internal environment mainly by the pineal gland, present in most vertebrates. Non-endocrine extrapineal locations have not been documented. This molecule with pleiotropic bioactions regulates the circadian rhythm, antioxidant, anti-inflammatory, immunostimulant, cardioprotective, antidiabetic, antiobesity, neuroprotective, and antiaging actions. Furthermore, in recent years, many studies have described the key role of melatonin in the prevention and development of cancer. The objective of this narrative review is to describe the different mechanisms through which melatonin exerts its action as an adjuvant in the modulation of carcinogenesis. The general anticarcinogenic mechanisms include epigenetic control, modulation of cell proliferation, regulation of cell cycle, induction of apoptosis, and telomerase inhibition. Melatonin also exerts antiestrogenic activity, which is particularly significant in hormone-dependent tumors, regulating the expression and transactivation of the estrogen receptor, and modulating the enzymes involved in the local synthesis of estrogens. Modulation of metastasis by melatonin includes increased expression of cell adhesion molecules such as E-cadherin and β1-integrin, inhibition of angiogenesis, and control of fat metabolism by inhibiting the uptake of fatty acids by membrane transporters. Finally, immunomodulatory properties include enhanced production of anti-inflammatory interleukins and other cytokines in lymphocytes and monocytes and modulation of antioxidant activity by neutralizing free radicals. Despite all the mentioned properties, the use of melatonin in daily clinical practice is very limited, and additional studies are needed to better establish the role of this hormone in oncological clinical applications against different types of cancer.
Hepatocellular carcinoma (HCC) stands as the primary cause of liver cancers, with limited treatment options outside of surgical resection or transplant. Photodynamic therapy (PDT) using indocyanine green (ICG) as a photosensitizer offers a promising therapeutic option for HCC. ICG PDT has demonstrated efficacy in vitro and
Renal cell carcinoma (RCC), being the most common type of renal malignancy, accounting for 85% of its incidence, poses a significant threat to human health. Although progress has been made in RCC diagnosis and management, problems of delayed detection and treatment failure remain in traditional methods. In the development of material research, biopolymers have emerged as significant players in medical practices, demonstrating considerable potential in the management of kidney cancer. Specifically, bioactive polymers have been proven to have numerous advantages over traditional methods, finding prosperous applications in diverse areas such as imaging detection, chemotherapy carrier, and prognostic estimation. However, the clinical value of some biopolymers still needs to be fully recognized in the RCC clinical pathway. This review summarizes recent studies about bioactive polymers’ application in RCC and further discusses its significance and constraints in clinical translational medicine and clinical trials. As our understanding of biopolymers grows, more advancements can be carried out in clinical practices.
Multiple myeloma is a neoplastic disorder of plasma cells typically afflicting older individuals. Despite significant improvements in induction therapy and outcomes for transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients, autologous stem cell transplant (ASCT) remains the standard of care for consolidation in transplant-eligible NDMM. Consequently, the optimal approach to stem cell mobilization remains critical. In this manuscript, we outline key updates to stem cell mobilization in NDMM patients. We describe the optimal number of cycles of induction prior to mobilization, emphasizing the need to balance the benefit of achieving improved depth of response by giving additional cycles of pre-transplant induction with the impact on stem cell yields. Additionally, we review ideal timing between the end of induction and initiation of mobilization to facilitate both a minimization of time off therapy as well as better communication and work flow between community providers and transplant centers. We also review different stem cell mobilization regimens with and without upfront CXCR4 inhibitors to optimize stem cell yields while considering both clinical outcomes and cost of care. Finally, we review optimal yields of CD34+ hematopoietic stem cells to minimize toxicity for ASCT and also consider optional utilization of stem cells for both salvage second ASCT and stem cell boosts for poor marrow function.
Aim: Cancer as a complex disease poses significant challenges for both diagnosis and treatment. Researchers have been exploring various avenues to find effective therapeutic strategies, with a particular emphasis on cellular signaling pathways and immunotherapy. One such pathway that has recently been suggested is the PD-1/PD-L1 pathway, which is an immune checkpoint signaling system that plays an important role in regulating the immune system and maintaining tissue homeostasis. Cancer cells exploit this pathway by producing PD-L1, which attaches to PD-1 on T cells, thus inhibiting immune responses and enabling the cancer cells to escape detection by the immune system. This study aimed to evaluate the role of the PD-1/PD-L1 pathway in cancer pathogenesis and treatment. Method: This study was performed based on the principles of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). All in vitro, in vivo, and clinical studies that were published in English have been considered during a thorough search of the Scopus, Web of Science, and PubMed databases without date restriction until March 2024. Results: According to the studies reviewed, the PD-1/PD-L1 signaling axis suggests promising therapeutic effects on various types of cancers such as non-small cell lung cancer, melanoma, breast cancer, hepatocellular carcinoma, squamous cell carcinoma, and colorectal cancer, among others. Additionally, research suggests that immune checkpoint inhibitors that block PD1/PD-L1, such as pembrolizumab, atezolizumab, nivolumab, durvalumab, cemiplimab, avelumab, etc., can effectively prevent tumor cells from escaping the immune system. Moreover, there might be a possible interaction between microbiome, obesity, etc. on immune mechanisms and on the immune checkpoint inhibitors (ICIs). Conclusion: Although we have gained considerable knowledge about ICIs, we are still facing challenges in effectively prescribing the appropriate ICIs for individual patients. This is largely due to the complex interactions between different intracellular pathways, which need to be thoroughly studied. To resolve this issue, it is necessary to conduct more reliable clinical trials that can produce a scientific consensus.
Ovarian cancer (OC) is the leading cause of death related to gynecologic malignancies, with recurrence occurring frequently despite significant advances in surgical interventions and chemotherapy. Therefore, novel therapies are necessary to improve the long-term prognosis of the disease. Immunotherapy holds promise in OC treatment by harnessing the potential of the immune system to combat neoplastic cells. The effectiveness of immunotherapy has been demonstrated in numerous cancers and subsequently integrated into clinical practice. However, despite initial preclinical findings suggesting an immunogenic microenvironment in OC, immune checkpoint inhibitors have not shown significant outcomes in clinical studies thus far. Further investigation is needed to fully understand the role of immunity in OC and to develop more effective therapeutic strategies, including combinatorial approaches and the identification of predictive biomarkers for more accurate patient selection for immunotherapy.
Aim: This study aimed to develop an m6A-related gene signature for predicting the prognosis of clear cell renal cell carcinoma (ccRCC) patients and explore its value in predicting the immunotherapy response.
Methods: In total, 530 ccRCC patients with gene expression data in the TCGA cohort were included and classified into the training (n = 371) and validation (n = 159) sets. Differential expression analyses of 23 m6A regulators between survivors and non-survivors were performed. Subsequently, an m6A-related gene signature was developed via LASSO Cox regression. All patients were categorized into two groups of m6A subtypes, i.e., low or high m6A score group. The Kaplan-Meier survival curves and Tumor Immune Dysfunction and Exclusion (TIDE) scores of the two m6A subtype groups were compared to measure the gene signature’s predictive value in prognosis and potential immunotherapy response, respectively.
Results: Eighteen m6A regulators were significantly differentially expressed between the survivors and non-survivors, and were also related to overall survival (OS). A gene signature containing five selected m6A methylation regulators (KIAA1429, METTL14, IGF2BP2, IGF2BP3, and SRSF2) was developed and showed favorable discrimination in the training (C-index 0.708) and validation (C-index 0.689) sets. Patients with low m6A scores had significantly better OS and lower TIDE scores than those with high m6A scores. Moreover, a robust MRI-based radiomic signature was developed to noninvasively predict the m6A subtype for each patient.
Conclusion: We demonstrated the prognostic value of five m6A regulators and constructed a gene signature for prognosis and immunotherapy response prediction among ccRCC patients. In addition, a radiomic signature was developed for noninvasive prediction of the m6A subtype. These findings may promote precision medicine and provide novel insights into the regulation of tumor immune microenvironment.
Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but aggressive primary liver cancer with a poor prognosis. A number of established clinical and pathologic factors correlate with prognosis, and this is reflected in the American Joint Committee on Cancer (AJCC) 8th Edition staging manual. Researchers have identified areas for improvement in staging and prognostication of ICC using more nuanced tools, including serum biomarkers, molecular profiling, immunophenotyping, and multimodal prognostic scoring systems. These data have led to proposals of novel staging systems that attempt to improve the correlation between stage and prognosis. More accurate staging tools may aid in treatment decisions that are tailored to each individual patient, to maximize therapy for individuals most likely to benefit and to avoid unnecessary toxicity and decision regret in those for whom aggressive treatment is unlikely to alter outcomes. Artificial intelligence and machine learning may help researchers develop new models that predict outcomes with more accuracy and precision.
Aim: This study explored the prognostic value of N-glycan biosynthesis (NGB) in lower-grade glioma (LGG) and aimed to develop a machine learning model for enhanced prognostic accuracy.
Method: LGG patient transcriptome data were analyzed to identify NGB-related genes. Consensus clustering identified subgroups based on NGB expression. A prognostic NGB signature (pNGB) was developed using machine learning. The pNGB score's association with cell proliferation, inflammation, treatment response, tumor recurrence, and the immune microenvironment was also explored.
Results: A 22-gene pNGB signature was identified, with MGAT1 and TUSC3 having the highest and lowest hazard ratios, respectively. Two distinct clusters (C1 and C2) with differential pNGB expression and survival outcomes were revealed. NGB pathway analysis indicated an overall poor prognosis, except for MGAT4C and TUSC3. The Enet-based survival model showed superior discriminatory power and reliability. The NGB risk score correlated with increased cell proliferation, inflammation, and altered immune landscape. Additionally, the score is linked to treatment response and tumor recurrence.
Conclusion: This study highlights the critical role of NGB in LGG progression and proposes a pNGB-based model for prognosis. The NGB risk score shows promise as a prognostic biomarker and potential therapeutic target in LGG.
Aim: Standard treatment includes post-surgical chemoradiotherapy and adjuvant temozolomide (TMZ) for glioblastoma (GBM). There is no consensus on the optimal duration for adjuvant TMZ. This study assessed whether prolonging adjuvant TMZ improved survival outcomes.
Methods: We retrospectively analyzed data of GBM patients who met inclusion criteria at our institute from September 2013 to December 2022. Patients who received 6 cycles of maintenance TMZ constituted the standard group, whereas those who underwent > 6 cycles were classified into the extended group. Kaplan-Meier method was used to estimate the median progression-free survival (PFS) and overall survival (OS). Independent predictors of OS and PFS were explored by Cox regression analyses.
Results: 100 patients were enrolled. Extended adjuvant TMZ significantly improved OS (28.0 vs. 10.0 months,
Conclusion: This study indicated that prolonged adjuvant TMZ significantly enhanced OS and PFS in GBM, and the adverse events were acceptable. The benefits were particularly notable in those with MGMT promoter methylation, solitary GBM, and high KPS. The optimal cycles of adjuvant TMZ require large prospective studies to further validate and identify which patient groups benefit the most based on molecular subtyping and clinical characteristics.
Hepatocellular carcinoma (HCC) is a primary liver cancer that arises in the setting of chronic liver inflammation and/or cirrhosis. Despite advancements in screening and treatment, the incidence and mortality of HCC continue to increase. Treatment for HCC is guided by a patient’s liver function, performance status, and extent of tumor burden. Patients with early-stage HCC are often treated with surgery, liver transplantation, or liver-directed therapy. Unfortunately, many patients have limited surgical options due to advanced-stage disease, recurrent disease after resection, or pre-existing moderate to severe liver dysfunction. These patients are subsequently treated with a combination of atezolizumab and bevacizumab, or durvalumab and tremelimumab. Operative management of HCC requires experienced surgeons and a multidisciplinary team of medical oncologists, radiation oncologists, and hepatologists for appropriate patient selection. Due to the complex management required for these patients, it is critical that the surgical management is informed by updated guidelines and data. We herein review the surgical management and treatment considerations for patients with HCC.
Hypertension is a known risk factor for clear cell renal cell carcinoma (ccRCC), yet the underlying mechanisms remain elusive. Studies have confirmed that the renin-angiotensin system (RAS) plays a role beyond regulating blood pressure, influencing various aspects of tumor development and metastasis. Generally, activation of the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin type 1 receptor (AT1R) axis elevates blood pressure and promotes tumor progression, while the activation of the angiotensin-converting enzyme 2 (ACE2)/[Ang-(1-7)]/Mas receptor (MasR) axis antagonizes these effects. Consequently, many cardiovascular drugs targeting the RAS may possess both hypotensive and antitumor properties. However, the role of RAS in ccRCC is controversial. To explore this, we reviewed the relevant literature. Surprisingly, apart from ACE2, the activation of RAS may facilitate the progression and metastasis of ccRCC. This unexpected finding suggests caution when using RAS inhibitors in ccRCC patients. This review provides an overview of the RAS, highlights research advances in RAS for ccRCC, elucidates the current status of RAS-targeted drugs in the treatment of ccRCC, and discusses the current challenges and future research directions in this field. In conclusion, the upregulation of other effector peptides and the activation of receptors in the RAS, apart from ACE2, may expedite ccRCC progression. Therefore, careful consideration is needed when using relevant drugs in ccRCC patients with hypertension. This synthesis of available evidence is crucial for informing the clinical management of ccRCC and guiding the development of novel therapeutic strategies.
The tumor microenvironment (TME) of breast cancer (BC) is depicted as an immunosuppressive dwelling that comprises a myriad of cell types embedded in the extracellular matrix. As one of the most abundant cell populations within the TME, cancer-associated fibroblasts (CAFs) play indispensable roles in increasing cancer aggressiveness and promoting resistance to standard-of-care therapies. Extracellular vesicles (EVs) represent a diverse array of biological nanoparticles, encompassing exosomes, microvesicles, and apoptotic bodies. In recent years, these cell-derived membranous structures have raised great interest as they can encapsulate numerous types of cellular cargo, such as proteins, lipids, and miRNAs. By transmitting bioactive content to recipient cells, EVs play pivotal roles in intercellular communication between CAFs and tumor cells. EVs secreted from tumor cells typically activate resident fibroblasts to acquire a myofibroblastic phenotype, while EVs diffused by CAFs, in turn, substantially increase the progression of BC. This review summarizes the latest findings to highlight the functional role of EV cargo, especially miRNAs, in the regulatory network. A better understanding of the EV-mediated cell-cell interactions is crucial to achieving effective treatment in patients with BC.
Metabolic reprogramming is an intrinsic characteristic of cancer, contributing to its establishment and progression, survival, high proliferation rates, and increased migratory and invasive potential; tumor cells establish an intimate relationship with the surrounding microenvironment, where sustained communication allows the stromal fraction of the tumor microenvironment (TME) to supply energetic substrates and facilitate the biosynthesis of macromolecules, thereby promoting tumor progression. In this context, extracellular vesicles (EVs) emerge as potential communication vehicles, carrying inside content reflecting the cellular environment of origin and thus modulating the phenotype of recipient cells. The potential of EVs as modulators in the TME has been highlighted and is now consensual; however, most available articles have focused on revealing the effect of EVs in modulating tumor phenotypes and signaling pathways in tumor cells. Regarding the metabolic modulation sustained by EVs, studies have demonstrated the role of cancer cells’ EVs as modulators of surrounding cells, like immune cells, fibroblasts, and adipocytes. Therefore, this review aims to: i. highlight the most recent studies evaluating the role of cellular vesicles released by those cells within the microenvironment in the metabolic reprogramming of cancer cells; ii. compile scientific evidence proposing how EVs could modulate the metabolic profile of tumor stem cells and lymphocytes, particularly given the lack of studies focused on such approaches; and iii. highlight possible effects of vesicles, as the metabolic modulation induced by these vesicles could have anticancer potential.
The molecular classification of breast cancer plays a pivotal role in developing personalized treatment strategies, with the aim of improving therapeutic outcomes. Despite significant advancements, current diagnostic workflows are hindered by several challenges, including pre-analytical variability, interpretive ambiguity, and inconsistencies in threshold definitions, particularly in cases involving human epidermal growth factor receptor 2 (HER2)-low breast cancer. In this context, liquid biopsy technologies have emerged as promising tools for refining breast cancer diagnostics. Techniques such as circulating tumor DNA and circulating tumor cell analysis provide a non-invasive approach to assessing tumor-associated biomarkers. These methodologies are particularly advantageous for analyzing low-abundance materials, such as formalin-fixed paraffin-embedded samples and liquid biopsies, thus enhancing the precision of molecular classification and informing more targeted therapeutic decisions for breast cancer patients. This review aims to explore the potential of liquid biopsy in addressing the limitations of current diagnostic practices, with a specific focus on its application in HER2-low breast cancer. Furthermore, it advocates for a transition toward high-throughput RNA-based screening and quantification, which may address critical unmet clinical needs.
Esophageal cancer is a highly lethal cancer with notable global variations in incidence and risk factors. In the U.S., it ranks as the fifth most common gastrointestinal cancer, with around 16,940 new cases annually, while globally, it is the sixth most common cancer. Significant regional disparities are highlighted by the "esophageal cancer belt" across northern Iran, southern Russia, central Asia, and northern China, where squamous cell carcinoma (SCC) dominates, comprising 90% of cases. In contrast, the U.S. has seen a rise in esophageal adenocarcinoma, primarily due to obesity and gastroesophageal reflux disease, with SCC rates declining as tobacco and alcohol use decrease. Key trials have shaped current treatment approaches. The CROSS trial (2012) showed a survival advantage with neoadjuvant chemoradiotherapy (carboplatin/paclitaxel with radiotherapy) plus surgery over surgery alone, extending median overall survival (OS) from 24 to 49.4 months. The FLOT4 trial (2017) established perioperative FLOT chemotherapy as superior to ECF/ECX, with median OS increasing from 35 to 50 months. The Neo-AEGIS trial (2020) found comparable OS between the CROSS and perioperative chemotherapy regimens, supporting treatment flexibility. Recently, the ESOPEC trial (ASCO 2024) demonstrated a median OS benefit with perioperative FLOT (66 months) over CROSS (37 months) in resectable esophageal adenocarcinoma, positioning FLOT as the preferred strategy. These findings highlight the value of tailored, multimodal therapies in enhancing survival and quality of life for esophageal adenocarcinoma patients. Future research will explore immunotherapy's role and the potential to omit surgery in patients achieving a complete pathological response.
Radiotherapy (RT) is a cornerstone in the management of head and neck cancer (HNC), with the choice of RT type profoundly affecting patient outcomes, symptom severity, and quality of life (QoL). This review examines photon and proton RT types for HNC, focusing on dosimetric advantages, efficacy, and side effect profiles. Understanding these factors is crucial to minimizing adverse effects, enhancing QoL for patients, and effectively improving oncology’s clinical praxis. While photon-based therapies, such as intensity-modulated radiation therapy and volumetric modulated arc therapy, are widely used and effective, proton therapy, including intensity-modulated proton therapy (IMPT) and pencil beam scanning (PBS), offers distinct physical advantages. Photon therapies allow for precise dose distribution but often result in higher integral doses to surrounding healthy tissues. In contrast, protons enable highly conformal dose distributions with minimal exit dose beyond the target, a property that significantly reduces radiation exposure to organs at risk. Background research and comparative analysis demonstrate that proton therapy techniques, particularly IMPT and PBS, outperform photon-based methods in sparing critical structures and thus reducing acute and late treatment-related morbidities, such as xerostomia and dysphagia. As a consequence, patient-reported outcome measures and the overall QoL results suggest that proton therapies lead to better treatment results with fewer severe side effects and improved symptom management. In conclusion, proton therapy, particularly IMPT, shows promise as a treatment of choice for HNC, minimizing toxicities and enhancing QoL. However, continued research and evidence-based approaches are still essential to properly validate and refine proton therapy applications in HNC treatment paradigms and also effectively translate them into future clinical practice.
Objective: To use bioinformatics analysis and in vitro and in vivo experiments to study the biological role of ALKBH3 in lung adenocarcinoma.
Methods: Bioinformatics analysis of ALKBH3 was performed using databases. ALKBH3 expression in lung adenocarcinoma and adjacent tissues was detected by qPCR (quantitative polymerase chain reaction), western blotting, and immunohistochemistry. Stable transformed A549 cells with low expression of ALKBH3 were constructed. The effects of knockdown of ALKBH3 on the proliferation, migration, and invasion of lung adenocarcinoma A549 cells were detected by CCK-8, cell scratch, and transwell invasion assays, respectively. The effects of ALKBH3 on the proliferation of A549 cells in vivo were detected using subcutaneous tumorigenesis in nude mice.
Results: Bioinformatics analysis showed that ALKBH3 has diagnostic value in tumors such as lung adenocarcinoma, the expression of ALKBH3 is related to immune cell infiltration, ALKBH3 interacts with ASCC family molecules, and ALKBH3 is involved in the demethylation of DNA and RNA. The expression of ALKBH3 in lung adenocarcinoma was higher than that in adjacent tissues (P < 0.05). CCK-8, wound healing and transwell assays showed that ALKBH3 knockdown significantly inhibited the proliferation, migration, and invasion of A549 cells in vitro (P < 0.01). ALKBH3 knockdown also significantly inhibited the growth of subcutaneous tumors in nude mice (P < 0.01).
Conclusions: ALKBH3 is a potential diagnostic marker for lung adenocarcinoma. Results in vivo and in vitro showed that knocking down ALKBH3 could inhibit the proliferation, migration, invasion, and subcutaneous tumorigenesis of lung adenocarcinoma A549 cells.