Exploring Gut Microbiome Composition and Circulating Microbial DNA Fragments in Patients with Stage II/III Colorectal Cancer: A Comprehensive Analysis.

BACKGROUND: Colorectal cancer (CRC) significantly contributes to cancer-related mortality, necessitating the exploration of prognostic factors beyond TNM staging. This study investigates the composition of the gut microbiome and microbial DNA fragments in stage II/III CRC. METHODS: A cohort of 142 patients with stage II/III CRC and 91 healthy controls underwent comprehensive microbiome analysis. Fecal samples were collected for 16S rRNA sequencing, and blood samples were tested for the presence of microbial DNA fragments. De novo clustering analysis categorized individuals based on their microbial profiles. Alpha and beta diversity metrics were calculated, and taxonomic profiling was conducted. RESULTS: Patients with CRC exhibited distinct microbial composition compared to controls. Beta diversity analysis confirmed CRC-specific microbial profiles. Taxonomic profiling revealed unique taxonomies in the patient cohort. De novo clustering separated individuals into distinct groups, with specific microbial DNA fragment detection associated with certain patient clusters. CONCLUSIONS: The gut microbiota can differentiate patients with CRC from healthy individuals. Detecting microbial DNA fragments in the bloodstream may be linked to CRC prognosis. These findings suggest that the gut microbiome could serve as a prognostic factor in stage II/III CRC. Identifying specific microbial markers associated with CRC prognosis has potential clinical implications, including personalized treatment strategies and reduced healthcare costs. Further research is needed to validate these findings and uncover underlying mechanisms.

Opioid burden in patients with inoperable pancreatic adenocarcinoma and the development of a multivariable risk prediction model for opioid use: A retrospective cohort study.

INTRODUCTION: Risk prediction models to guide patient selection for early pre-emptive endoscopic ultrasound guided coeliac plexus neurolysis are lacking. This study aimed to determine in patients with inoperable pancreatic cancer: (1) opioid burden, (2) the relationship between opioid use and all-cause mortality, (3) risk factors for opioid use, and (4) develop and internally validate a risk prediction model for opioid use at three months. METHODS: This was a single-centre retrospective cohort study of patients with confirmed pancreatic cancer. Cox proportional hazard regression estimated the association between opioid use at baseline and all-cause mortality. Logistic regression estimated the associations between clinical and radiological variables with opioid use by three months. Two risk prediction models were developed for opioid use (clinical and clinical-radiological). Model discrimination and calibration was assessed. RESULTS: In total, 383 patients with inoperable pancreatic cancer were included. Prevalence of pain ranged between 37% and 47% at three monthly intervals in the first year of diagnosis. Opioid use at baseline was associated with poorer survival. Age, pain at presentation, performance status, tumour distance from the right ganglion, the anterior-posterior and the latero-lateral tumour dimensions were independent risk factors for the opioid use at three months. The Area Under Curve (AUC) for the clinical and clinical-radiological models was 0.81 and 0.84, respectively. Models were well calibrated. CONCLUSIONS: Opioid use is prevalent in patients with pancreatic cancer, associated with poor prognosis, and can be predicted based on clinical and radiological variables. External validation of this predictive model is required.

Telemedicine in Care of Sarcoma Patients beyond the COVID-19 Pandemic: Challenges and Opportunities.

BACKGROUND: The COVID-19 pandemic has created a challenging environment for sarcoma patients. Most oncology societies published guidelines or recommendations prioritizing sarcoma patients and established telehealth as an efficient method of approaching them. The aim of this review is the assessment of current evidence regarding the utilization of telemedicine in diagnosis, treatment modalities, telerehabilitation and satisfaction among sarcoma patients and healthcare providers (HP). METHODS: This systematic review was carried out using the databases PubMed and Ovid MEDLINE according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: The application of telemedicine to the management of sarcoma has yielded improved clinical and psychological outcomes. Specifically, significant progress has been demonstrated in the areas of tele-oncology and telerehabilitation during the last decade, and the COVID-19 outbreak has accelerated this transition toward them. Telehealth has been proven efficient in a wide spectrum of applications from consultations on physical therapy and psychological support to virtual care symptom management. Both HP and patients reported satisfaction with telehealth services at levels comparable to in-person visits. CONCLUSIONS: Telehealth has already unveiled many opportunities in tailoring individualized care, and its role in the management of sarcoma patients has been established in the post-COVID-19 era, as well.

Safety and efficacy of immune checkpoint blockade in patients with advanced nonsmall cell lung cancer and brain metastasis.

The presence of brain metastases (BM) is a negative prognostic factor for patients with advanced nonsmall cell lung cancer (NSCLC). Their incidence seems to be higher in patients with oncogene-driven tumours, especially those with EGFR-mutated or ALK-rearranged tumours. Although targeted treatments demonstrate significant efficacy regarding BM, they only apply to a minority of NSCLC patients. On the other hand, systemic therapies for nononcogenic-driven NSCLC with BM have shown limited clinical benefit. In recent years, immunotherapy alone or combined with chemotherapy has been adopted as a new standard of care in first-line therapy. This approach seems to be beneficial to patients with BM in terms of efficacy and toxicity. Combined immune checkpoint inhibition as well as the combination of immunotherapy and radiation therapy show promising results with significant, but overall acceptable toxicity. A pragmatic approach of allowing enrolment of patients with untreated or symptomatic BM in randomised trials evaluating immune checkpoint inhibitors strategies, possibly coupled with central nervous system-related endpoints may be needed to generate data to refine treatment for this patient population.

The Fractal Viewpoint of Tumors and Nanoparticles.

Even though the promising therapies against cancer are rapidly improved, the oncology patients population has seen exponential growth, placing cancer in 5th place among the ten deadliest diseases. Efficient drug delivery systems must overcome multiple barriers and maximize drug delivery to the target tumors, simultaneously limiting side effects. Since the first observation of the quantum tunneling phenomenon, many multidisciplinary studies have offered quantum-inspired solutions to optimized tumor mapping and efficient nanodrug design. The property of a wave function to propagate through a potential barrier offer the capability of obtaining 3D surface profiles using imaging of individual atoms on the surface of a material. The application of quantum tunneling on a scanning tunneling microscope offers an exact surface roughness mapping of tumors and pharmaceutical particles. Critical elements to cancer nanotherapeutics apply the fractal theory and calculate the fractal dimension for efficient tumor surface imaging at the atomic level. This review study presents the latest biological approaches to cancer management based on fractal geometry.

Resistance to TKIs in EGFR-Mutated Non-Small Cell Lung Cancer: From Mechanisms to New Therapeutic Strategies.

Resistance to tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in advanced mutant Non-Small Cell Lung Cancer (NSCLC) constitutes a therapeutic challenge. This review intends to summarize the existing knowledge about the mechanisms of resistance to TKIs in the context of EGFR mutant NSCLC and discuss its clinical and therapeutic implications. EGFR-dependent and independent molecular pathways have the potential to overcome or circumvent the activity of EGFR-targeted agents including the third-generation TKI, osimertinib, negatively impacting clinical outcomes. CNS metastases occur frequently in patients on EGFR-TKIs, due to the inability of first and second-generation agents to overcome both the BBB and the acquired resistance of cancer cells in the CNS. Newer-generation TKIs, TKIs targeting EGFR-independent resistance mechanisms, bispecific antibodies and antibody-drug conjugates or combinations of TKIs with other TKIs or chemotherapy, immunotherapy and Anti-Vascular Endothelial Growth Factors (anti-VEGFs) are currently in use or under investigation in EGFR mutant NSCLC. Liquid biopsies detecting mutant cell-free DNA (cfDNA) provide a window of opportunity to attack mutant clones before they become clinically apparent. Overall, EGFR TKIs-resistant NSCLC constitutes a multifaceted therapeutic challenge. Mapping its underlying mutational landscape, accelerating the detection of resistance mechanisms and diversifying treatment strategies are essential for the management of the disease.

The changing epidemiology of hepatocellular carcinoma in Greece.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, and is attributable mainly to viral hepatitis, alcohol and nonalcoholic fatty liver disease. METHODS: Three hundred Greek patients diagnosed with HCC between 2000 and 2019 were retrospectively evaluated for patient and HCC characteristics. Patients were classified as before 2011 (A) or after 2011 (B) and HCC risk factors were compared with historic Greek cohorts. RESULTS: The median age was 64 years and 86% were male; 45% had chronic hepatitis B virus (HBV) infection, 26% chronic hepatitis C virus (HCV) infection, and 30% non-viral liver diseases (nvLD). No change was observed among liver diseases between periods A and B. However, there was a trend towards a decrease in virally and an increase in non-virally induced HCC (P=0.075). Patients in period B (vs. A) were more likely to be diagnosed with fewer (<3, P=0.006) and smaller (<3 cm, P=0.005) nodules. Compared with 1558 Greek HCC patients from 1974-2000, there was a decrease in HBV and an increase in HCV and nvLD-related HCCs (P<0.001). CONCLUSIONS: In Greece, after 2000, there was a decrease in the proportion of HBV and an increase in the proportion of HCV and nvLD-related HCC, while over the last 2 decades there has been a trend towards a decrease in virally and an increase in non-virally induced HCC. Since 2011, HCC is being diagnosed at an earlier stage, possibly reflecting improved surveillance strategies.

Matched Analyses of Brain Metastases versus Primary Non-Small Cell Lung Cancer Reveal a Unique microRNA Signature.

Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections.

Resectable Colorectal Cancer: Current Perceptions on the Correlation of Recurrence Risk, Microbiota and Detection of Genetic Mutations in Liquid Biopsies.

Metastatic colorectal cancer (mCRC) remains a highly lethal malignancy, although considerable progress has resulted from molecular alterations in guiding optimal use of available treatments. CRC recurrence remains a great barrier in the disease management. Hence, the spotlight turns to newly mapped fields concerning recurrence risk factors in patients with resectable CRC with a focus on genetic mutations, microbiota remodeling and liquid biopsies. There is an urgent need for novel biomarkers to address disease recurrence since specific genetic signatures can identify a higher or lower recurrence risk (RR) and, thus, be used both as biomarkers and treatment targets. To a large extent, CRC is mediated by the immune and inflammatory interplay of microbiota, through intestinal dysbiosis. Clarification of these mechanisms will yield new opportunities, leading not only to the appropriate stratification policies, but also to more precise, personalized monitoring and treatment navigation. Under this perspective, early detection of post-operative CRC recurrence is of utmost importance. Ongoing trials, focusing on circulating tumor cells (CTCs) and, even more, circulating tumor DNA (ctDNA), seem to pave the way to a promising, minimally invasive but accurate and life-saving monitoring, not only supporting personalized treatment but favoring patients' quality of life, as well.

Hepatocellular Carcinoma: An Overview of the Changing Landscape of Treatment Options.

The last three years have seen remarkable progress in comprehending predisposing factors and upgrading our treatment arsenal concerning hepatocellular carcinoma (HCC). Until recently, there were no means to withstand the progression of viral hepatitis-associated liver cirrhosis to HCC. A deeper understanding of the molecular mechanism of the disease, the use of biomarkers, and the follow-up, allowed us to realize that conventional chemotherapy failing to increase survival in patients with advanced HCC tends to be exiled from clinical practice. Multi-kinase inhibitors (TKIs) such as sorafenib, lenvatinib targeting mainly the vascular endothelial growth factor receptors 1-3 VEGFRs 1-3 provided until recently the standard of care for these patients, as first- or second-line treatment. Since May 2020, the atezolizumab plus bevacizumab combination (immunotherapy plus anti-VEGF) has become the new reference standard in first-line HCC treatment. Additionally, anti-programmed cell death protein 1 (anti-PD-1) immunotherapy can be used as a second-line treatment following first-line treatment's failure. Phase III clinical trials have recently suggested the efficacy of novel anti-angiogenic factors such as cabozantinib and ramucirumab as a second-line treatment option. With considerations about toxicity arising, clinical trials are investigating combinations of the aforementioned targeted therapies with immunotherapy as first-line treatment. This paper aims to perform a systematic review describing the evolving treatment options for HCC over the last decades, ranging from neoadjuvant treatment to systemic therapy of advanced-stage HCC. With the landscape of HCC treatment shifting towards novel agents the forming of a new therapeutic algorithm for HCC seems to be imperative.

Immunotherapy for the treatment of metastatic small cell lung cancer: Focus on pembrolizumab.

AREAS COVERED: The current evidence on the role of pembrolizumab for patients with extensive SCLC is reviewed in this article. Particularly, preclinical and clinical data from phase I/II and III clinical trials, which evaluate the efficacy and toxicity of pembrolizumab for these patients, are summarized based on PubMed/MEDLINE search and relevant articles. In addition, future perspectives on the emerging role of immunotherapy for SCLC are highlighted in light of potentially useful biomarkers. EXPERT COMMENTARY: Pembrolizumab shows an excellent toxicity profile in recent studies, and significantly prolonged progression-free survival (PFS) but not overall survival (OS) in the phase III clinical trial KN604, in contrast to atezolizumab and durvalumab. The latter two agents have already been approved and incorporated in the daily clinical practice. Further research should be conducted so that phase III clinical trials can validate the potential clinical benefit of this checkpoint inhibitor in combination with other active agents and establish its role in the metastatic setting of SCLC.

Real Impact of Novel Immunotherapy Drugs in Cancer. The Experience of 10 Last Years.

Intense research on immunotherapy has been conducted during recent years. As advances in the field have started changing the landscape of cancer therapy, it is necessary to assess the impact of immunotherapeutic modalities in the treatment of various cancers. Ten years ago, in 2011, ipilimumab was the first of the newest immunotherapeutic drugs against cancer to be approved by the FDA. Then several drugs followed and formed a therapeutic arsenal to fight cancer. Initial studies were performed on metastatic patients, but there are currently several studies in patients with potentially curable cancers. All these developments have created a new environment for oncology which we will present in this article. This review examines the current evidence related to the impact of immunotherapy on various cancers and discusses its potential clinical and research implications, including its effectiveness in comparison to other treatment modalities (chemotherapy, radiotherapy), its toxicity and prospective research opportunities. While constant updates and further research is critical to understand the impact of immunotherapy in cancer therapy, not only does it seem to be important to assess the current state of knowledge highlighting the success but also to determine the challenging aspects of cancer immunotherapy.

Brain and bone marrow metastases from rectal cancer.

Despite the development of new treatment options based on the molecular characterization of colorectal cancer, 20% of patients present de novo metastatic disease, whereas 30-40% of patients who receive curative treatment relapse during follow up. Herein, we report 2 cases with rectal cancer that developed uncommon sites of metastasis; the first patient had an isolated breast metastasis, while the second patient developed bone marrow infiltration with synchronous brain metastases. In order to evaluate the uncommon metastatic pattern of rectal cancer, we detected and enumerated circulating tumor cells (CTCs) using both immunofluorescence and real-time reverse transcriptase polymerase chain reaction in these patients' peripheral blood. The procedure revealed the presence of CTCs, positive for CEACAM5 but negative for epithelial phenotype (EpCAM-), that might explain the patients' metastatic potential and survival.

Bridging clinic: The initial medical management of patients with newly diagnosed pancreatic cancer.

Pancreatic cancer is the 11th most common cancer in the UK and has the worst prognosis of any tumour with minimal improvements in survival over recent decades. As most patients are either ineligible for surgery or may decline chemotherapy, the emphasis is on control of symptoms and management of complications such as poor nutritional status. The time period between informing the patient of their diagnosis and commencing cancer treatments presents a valuable opportunity to proactively identify and treat symptoms to optimise patients' overall well-being. The 'bridging clinic', delivered by a range of healthcare professionals from gastroenterologists to nurse practitioners, can provide this interface where patients are first informed of their diagnosis and second supportive therapies offered. In this article, we provide a structure for instituting such supportive therapies at the bridging clinic. The components of the clinic are summarised using the mnemonic INDASH (Information/Nutrition/Diabetes and Depression/Analgesia/Stenting/Hereditary) and each is discussed in detail below.

Dietary Fiber and the Risk of Pancreatic Cancer.

OBJECTIVES: High dietary fiber may protect against pancreatic ductal adenocarcinoma (PDAC). We investigated associations between fiber intake and the risk of PDAC using for the first time 7-day food diaries. METHODS: Participants in the European Prospective Investigation Into Cancer-Norfolk completed the 7-day food diaries at recruitment. The cohort was followed up for 17 years to identify those who developed PDAC. Participants were divided into quintiles of fiber intake, and hazard ratios (HR) were estimated with their 95% confidence intervals (CIs). Fiber was tested for effect modification of high red and processed meat intake and smoking and the risk of PDAC. RESULTS: No significant associations for any quintiles of intake (HR Q5 vs Q1, 1.08; 95% CI, 0.56-2.08) were detected with no trend across quintiles. A high-fiber diet modified positive associations between red and processed meats with the development of PDAC (HR trends, 0.89 [95% CI, 0.47-1.69] and 1.02 [95% CI, 0.55-1.88], respectively) but not those with lower fiber intake. Fiber intake did not modify the risk of PDAC in past and current smokers. CONCLUSION: The findings do not suggest that fiber protects against PDAC, although it may decrease potential deleterious effects of meats.

Pain in Patients with Pancreatic Cancer: Prevalence, Mechanisms, Management and Future Developments.

Pain affects approximately 80% of patients with pancreatic cancer, with half requiring strong opioid analgesia, namely: morphine-based drugs on step three of the WHO analgesic ladder (as opposed to the weak opioids: codeine and tramadol). The presence of pain is associated with reduced survival. This article reviews the literature regarding pain: prevalence, mechanisms, pharmacological, and endoscopic treatments and identifies areas for research to develop individualized patient pain management pathways. The online literature review was conducted through: PubMed, Clinical Key, Uptodate, and NICE Evidence. There are two principal mechanisms for pain: pancreatic duct obstruction and pancreatic neuropathy which, respectively, activate mechanical and chemical nociceptors. In pancreatic neuropathy, several histological, molecular, and immunological changes occur which correlate with pain including: transient receptor potential cation channel activation and mast cell infiltration. Current pain management is empirical rather etiology-based and is informed by the WHO analgesic ladder for first-line therapies, and then endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with resistant pain. For EUS-CPN, there is only one clinical trial reporting a benefit, which has limited generalizability. Case series report pancreatic duct stenting gives effective analgesia, but there are no clinical trials. Progress in understanding the mechanisms for pain and when this occurs in the natural history, together with assessing new therapies both pharmacological and endoscopic, will enable individualized care and may improve patients' quality of life and survival.

Carnitine modulates crucial myocardial adenosine triphosphatases and acetylcholinesterase enzyme activities in choline-deprived rats.

Choline is an essential nutrient, and choline deficiency has been associated with cardiovascular morbidity. Choline is also the precursor of acetylcholine (cholinergic component of the heart's autonomic nervous system), whose levels are regulated by acetylcholinesterase (AChE). Cardiac contraction-relaxation cycles depend on ion gradients established by pumps like the adenosine triphosphatases (ATPases) Na(+)/K(+)-ATPase and Mg(2+)-ATPase. This study aimed to investigate the impact of dietary choline deprivation on the activity of rat myocardial AChE (cholinergic marker), Na(+)/K(+)-ATPase, and Mg(2+)-ATPase, and the possible effects of carnitine supplementation (carnitine, structurally relevant to choline, is used as an adjunct in treating cardiac diseases). Adult male albino Wistar rats were distributed among 4 groups, and were fed a standard or choline-deficient diet for one month with or without carnitine in their drinking water (0.15% w/v). The enzyme activities were determined spectrophotometrically in the myocardium homogenate. Choline deficiency seems to affect the activity of the aforementioned parameters, but only the combination of choline deprivation and carnitine supplementation increased myocardial Na(+)/K(+)-ATPase activity along with a concomitant decrease in the activities of Mg(2+)-ATPase and AChE. The results suggest that carnitine, in the setting of choline deficiency, modulates cholinergic myocardial neurotransmission and the ATPase activity in favour of cardiac work efficiency.