Clinical, Pathological and Molecular Insights on KRAS, NRAS, BRAF, PIK3CA and TP53 Mutations in Metastatic Colorectal Cancer Patients from Northeastern Romania.

Mutations in RAS, BRAF, PIK3CA, and TP53 are well-established genetic abnormalities in metastatic colorectal cancer (mCRC). However, limited information is available for patients from Eastern Europe, including Romania. In this retrospective analysis, we investigated 104 mCRC patients from the Northeastern region of Romania to determine the frequency, distribution, coexistence, and clinicopathological and molecular correlations of these mutations. TP53 was the most frequently mutated gene (73.1%), followed by KRAS (45.2%) and PIK3CA (6.7%). Patients with KRAS mutant tumors and wild-type TP53 genotype were found to have no personal history of gastrointestinal cancer (p = 0.02, p = 0.007). KRAS mutations in exon 3 were associated with the female gender (p = 0.02) and the absence of lymph node invasion (p = 0.02). PIK3CA mutations were linked to the absence of lymph node invasion (p = 0.006). TP53 mutations were associated with KRAS mutations in exon 2 (p = 0.006), ulcerated histopathologic type (p = 0.04), and G2 differentiation (p = 0.01). It provides novel insights into genetic variations specific to the population from Northeastern Romania, which has been underrepresented in previous studies within Eastern Europe. Furthermore, our findings enable the development of genetic profiles in a developing country with limited access to specialized genetic tests and facilitate comparisons with other populations.

The Roles of Imaging Biomarkers in the Management of Chronic Neuropathic Pain.

Chronic neuropathic pain (CNP) affects around 10% of the general population and has a significant social, emotional, and economic impact. Current diagnosis techniques rely mainly on patient-reported outcomes and symptoms, which leads to significant diagnostic heterogeneity and subsequent challenges in management and assessment of outcomes. As such, it is necessary to review the approach to a pathology that occurs so frequently, with such burdensome and complex implications. Recent research has shown that imaging methods can detect subtle neuroplastic changes in the central and peripheral nervous system, which can be correlated with neuropathic symptoms and may serve as potential markers. The aim of this paper is to review available imaging methods used for diagnosing and assessing therapeutic efficacy in CNP for both the preclinical and clinical setting. Of course, further research is required to standardize and improve detection accuracy, but available data indicate that imaging is a valuable tool that can impact the management of CNP.

Wnt/IL-1ß/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5.

Malignant pleural mesothelioma (MPM) is a tumor with high chemoresistance and poor prognosis. MPM-initiating cells (ICs) are known to be drug resistant, but it is unknown if and how stemness-related pathways determine chemoresistance. Moreover, there are no predictive markers of IC-associated chemoresistance. Aim of this work is to clarify if and by which mechanisms the chemoresistant phenotype of MPM IC was due to specific stemness-related pathways. We generated MPM IC from primary MPM samples and compared the gene expression and chemo-sensitivity profile of IC and differentiated/adherent cells (AC) of the same patient. Compared to AC, IC had upregulated the drug efflux transporter ABCB5 that determined resistance to cisplatin and pemetrexed. ABCB5-knocked-out (KO) IC clones were resensitized to the drugs in vitro and in patient-derived xenografts. ABCB5 was transcriptionally activated by the Wnt/GSK3ß/ß-catenin/c-myc axis that also increased IL-8 and IL-1ß production. IL-8 and IL-1ß-KO IC clones reduced the c-myc-driven transcription of ABCB5 and reacquired chemosensitivity. ABCB5-KO clones had lower IL-8 and IL-1ß secretion, and c-myc transcriptional activity, suggesting that either Wnt/GSK3ß/ß-catenin and IL-8/IL-1ß signaling drive c-myc-mediated transcription of ABCB5. ABCB5 correlated with lower time-to-progression and overall survival in MPM patients treated with cisplatin and pemetrexed. Our work identified multiple autocrine loops linking stemness pathways and resistance to cisplatin and pemetrexed in MPM IC. ABCB5 may represent a new target to chemosensitize MPM IC and a potential biomarker to predict the response to the first-line chemotherapy in MPM patients.

What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg.

Identification of multidrug (MDR) efflux transporters that belong to the ATP-Binding Cassette (ABC) superfamily, represented an important breakthrough for understanding cancer multidrug resistance (MDR) and its possible overcoming. However, recent data indicate that drug resistant cells have a complex intracellular physiology that involves constant changes in energetic and oxidative-reductive metabolic pathways, as well as in the molecular circuitries connecting mitochondria, endoplasmic reticulum (ER) and lysosomes. The aim of this review is to discuss the key molecular mechanisms of cellular reprogramming that induce and maintain MDR, beyond the presence of MDR efflux transporters. We specifically highlight how cancer cells characterized by high metabolic plasticity - i.e. cells able to shift the energy metabolism between glycolysis and oxidative phosphorylation, to survive both the normoxic and hypoxic conditions, to modify the cytosolic and mitochondrial oxidative-reductive metabolism, are more prone to adapt to exogenous stressors such as anti-cancer drugs and acquire a MDR phenotype. Similarly, we discuss how changes in mitochondria dynamics and mitophagy rates, changes in proteome stability ensuring non-oncogenic proteostatic mechanisms, changes in ubiquitin/proteasome- and autophagy/lysosome-related pathways, promote the cellular survival under stress conditions, along with the acquisition or maintenance of MDR. After dissecting the complex intracellular crosstalk that takes place during the development of MDR, we suggest that mapping the specific adaptation pathways underlying cell survival in response to stress and targeting these pathways with potent pharmacologic agents may be a new approach to enhance therapeutic efficacy against MDR tumors.

Challenges and Opportunities in Preclinical Research of Synthetic Cannabinoids for Pain Therapy.

Cannabis has been used in pain management since 2900 BC. In the 20th century, synthetic cannabinoids began to emerge, thus opening the way for improved efficacy. The search for new forms of synthetic cannabinoids continues and, as such, the aim of this review is to provide a comprehensive tool for the research and development of this promising class of drugs. Methods for the in vitro assessment of cytotoxic, mutagenic or developmental effects are presented, followed by the main in vivo pain models used in cannabis research and the results yielded by different types of administration (systemic versus intrathecal versus inhalation). Animal models designed for assessing side-effects and long-term uses are also discussed. In the second part of this review, pharmacokinetic and pharmacodynamic studies of synthetic cannabinoid biodistribution, together with liquid chromatography-mass spectrometric identification of synthetic cannabinoids in biological fluids from rodents to humans are presented. Last, but not least, different strategies for improving the solubility and physicochemical stability of synthetic cannabinoids and their potential impact on pain management are discussed. In conclusion, synthetic cannabinoids are one of the most promising classes of drugs in pain medicine, and preclinical research should focus on identifying new and improved alternatives for a better clinical and preclinical outcome.

Elder abuse and associated factors in eastern romania.

BACKGROUND: This article explores elder abuse in a hospitalised population. We wanted to identify details related to psychological and emotional abuse in the older population in our region and to determine the importance of the Elderly Abuse Suspicion Index (EASI© ) in comprehensive geriatric assessments. METHODS: This cross-sectional study conducted between March 2015 and May 2016 included 386 consecutive hospitalised patients over 65 years of age. All patients underwent a geriatric assessment, data were collected about their medical history, and the EASI© was administered to each. The main outcome was identifying the presence, the type of abuse and the factors associated with abuse. RESULTS: There were 21.5% of patients who suffered any form of abuse. Women were more frequently abused than men. Emotional abuse was the most common (60.2%) followed by neglect (53%) and physical abuse (22.91%); sexual abuse was absent in our study group. The abused patients had an impaired cognitive function (P = 0.034). They were also malnourished (P ≤ 0.001) and depressed (P = 0.001). The presence of peripheral artery disease, stroke, pneumonia, chronic kidney disease, musculoskeletal diseases and anxiety correlated with the presence of abuse. No statistically significant correlation was found between the degree of independence in instrumental activities of daily living and the presence of abuse (r = 0.105, P = 0.051). CONCLUSIONS: EASI is a tool for detecting elder abuse and should be included in the standard geriatric assessment to prevent ageism. The number of abused elderly patients is significant, and the multiple factors associated with abuse are diverse.

Consent for participating in clinical trials - Is it really informed?

The article explores the challenges of ensuring voluntary and informed consent which is obtained from potential research subjects in the north-eastern part of Romania. This study is one of the first empirical papers of this nature in Romania. The study used a quantitative survey design using the adapted Quality of Informed Consent (QuIC) questionnaire. The target population consisted of 100 adult persons who voluntarily enrolled in clinical trials. The informed consent form must contain details regarding the potential risks and benefits, the aim of the clinical trial, study design, confidentiality, insurance and contact details in case of additional questions. Our study confirmed that although all required information was included in the ICF, few clinical trial participants truly understood it. We also found that the most important predictive factor for a good subjective and objective understanding of the clinical trial was the level of education. Our study suggests that researchers should consider putting more effort in order to help clinical trials participants achieve a better understanding of the informed consent. In this way they will ensure that participants' decision-making is meaningful and that their interests are protected.

Preoperative frailty screening in elderly patients with non-small cell lung cancer surgery: an essential step for a good surgical outcome.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is a disease commonly diagnosed in the elderly, often in advanced stages. However, elderly patients with lung cancer can benefit from surgery, provided that postoperative risks are assessed appropriately before surgery. Frailty is a measure of age-related impaired functional status and a predictor of mortality and morbidity. However, its importance as a preoperative marker is not well defined. AREAS COVERED: This systematic review discusses the importance of preoperative frailty screening in elderly patients with NSCLC. A literature search was performed on the MEDLINE database in June 2023, and relevant studies on frailty or preoperative assessment of NSCLC which were published between 2000 and 2023 were retained and discussed in this review. EXPERT OPINION: Among the types of existing methods used to assess frailty those on the geriatric assessment seem to be the most appropriate; however, they are unable to fully capture the 'surgical' frailty; thus, other instruments should be developed and validated in NSCLC.

Inhibition of TRPM8 function by prostacyclin receptor agonists requires coupling to Gq/11 proteins.

BACKGROUND AND PURPOSE: The TRPM8 ion channel is involved in innocuous cold sensing and has a potent anti-inflammatory action. Its activation by lower temperature or chemical agonists such as menthol and icilin induces analgesic effects, reversing hypersensitivity and reducing chronic pain. On the other hand, prostacyclin (PGI2) enhances pain and inflammation by activating the IP receptors. Due to the critical roles of TRPM8 and IP receptors in the regulation of inflammatory pain, and considering their overlapping expression pattern, we analysed the functional interaction between human TRPM8 and IP receptors. EXPERIMENTAL APPROACH: We transiently expressed human TRPM8 channels and IP receptors in HEK293T cells and carried out intracellular calcium and cAMP measurements. Additionally, we cultured neurons from the dorsal root ganglia (DRGs) of mice and determined the increase in intracellular calcium triggered by the TRPM8 agonist, icilin, in the presence of the IP receptor agonist cicaprost, the IP receptor antagonist Cay10441, and the Gq/11 inhibitor YM254890. KEY RESULTS: Activation of IP receptors by selective agonists (cicaprost, beraprost, and iloprost) inhibited TRPM8 channel function, independently of the Gs-cAMP pathway. The potent inhibition of TRPM8 channels by IP receptor agonists involved Gq/11 coupling. These effects were also observed in neurons isolated from murine DRGs. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate an unusual signalling pathway of IP receptors by coupling to Gq/11 proteins to inhibit TRPM8 channel function. This pathway may contribute to a better understanding of the role of TRPM8 channels and IP receptors in regulating pain and inflammation.

The potential neuroprotective effects of cannabinoids against paclitaxel-induced peripheral neuropathy: in vitro study on neurite outgrowth.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a shared burden for 68.1% of oncological patients undergoing chemotherapy with Paclitaxel (PTX). The symptoms are intense and troublesome, patients reporting paresthesia, loss of sensation, and dysesthetic pain. While current medications focus on decreasing the symptom intensity, often ineffective, no medication is yet recommended by the guidelines for the prevention of CIPN. Cannabinoids are an attractive option, as their neuroprotective features have already been demonstrated in neuropathies with other etiologies, by offering the peripheral neurons protection against toxic effects, which promotes analgesia. Methods: We aim to screen several new cannabinoids for their potential use as neuroprotective agents for CIPN by investigating the cellular toxicity profile and by assessing the potential neuroprotective features against PTX using a primary dorsal root ganglion neuronal culture. Results: Our study showed that synthetic cannabinoids JWH-007, AM-694 and MAB-CHMINACA and phytocannabinoids Cannabixir® Medium dried flowers (NC1) and Cannabixir® THC full extract (NC2) preserve the viability of fibroblasts and primary cultured neurons, in most of the tested dosages and time-points. The combination between the cannabinoids and PTX conducted to a cell viability of 70%-89% compared to 40% when PTX was administered alone for 48 h. When assessing the efficacy for neuroprotection, the combination between cannabinoids and PTX led to better preservation of neurite length at all tested time-points compared to controls, highly drug and exposure-time dependent. By comparison, the combination of the cannabinoids and PTX administered for 24 h conducted to axonal shortening between 23% and 44%, as opposed to PTX only, which shortened the axons by 63% compared to their baseline values. Discussion and Conclusion: Cannabinoids could be potential new candidates for the treatment of paclitaxel-induced peripheral neuropathy; however, our findings need to be followed by additional tests to understand the exact mechanism of action, which would support the translation of the cannabinoids in the oncological clinical practice.

Lidocaine-Liposomes-A Promising Frontier for Transdermal Pain Management.

(1) Background: We aim to develop novel gel formulations for transdermal drug delivery systems in acute and inflammatory pain therapy. (2) Methods: We induced inflammation by the injection of λ-carrageenan on the hind paw of 80 Wistar male rats. The animals were randomized into eight groups of 10 rats each: C (placebo gel), E (EMLATM), L (lidocaine 2%), L-CD (lidocaine + cyclodextrin 2.5%), L-LP (lidocaine + liposomes 1.7%), L-CS (lidocaine + chitosan 4%), L-CSh (lidocaine + chitosan hydrochloride), and L-CS-LP (lidocaine + chitosan + liposomes). The behavior response was determined with a hot plate, cold plate, and algesimeter, each being performed at 30, 60, 120, 180, and 240 min after pain induction. At the end of the experiment, tissue samples were collected for histological assessment. (3) Results: L-LP had the greatest anesthetic effects, which was proven on the cold plate test compared to placebo and EMLATM (all p ≤ 0.001). L-CS-LP had a significant effect on cold plate evaluation compared to placebo (p ≤ 0.001) and on hot plate evaluation compared to EMLATM (p = 0.018). (4) Conclusions: L-LP is a new substance with a substantial analgesic effect demonstrated by the cold plate in the first 120 min. Further studies with more animals are needed to determine the maximum doses that can be applied for a better analgesia with minimum side effects.

JWH-182: a safe and effective synthetic cannabinoid for chemotherapy-induced neuropathic pain in preclinical models.

Chemotherapy-induced neuropathic pain (CINP), a condition with unmet treatment needs, affects over half of cancer patients treated with chemotherapeutics. Researchers have recently focused on the endocannabinoid system because of its critical role in regulating our bodies' most important functions, including pain. We used in vitro and in vivo methods to determine the toxicity profile of a synthetic cannabinoid, JWH-182, and whether it could be potentially effective for CINP alleviation. In vitro, we evaluated JWH-182 general toxicity, measuring fibroblast viability treated with various concentrations of compound, and its neuroprotection on dorsal root ganglion neurons treated with paclitaxel. In vivo, we performed an evaluation of acute and 28-day repeated dose toxicity in mice, with monitoring of health status and a complete histopathological examination. Finally, we evaluated the efficacy of JWH-182 on a CINP model in mice using specific pain assessment tests. JWH-182 has an acceptable toxicity profile, in both, in vitro and in vivo studies and it was able to significantly reduce pain perception in a CINP model in mice. However, the translation of these results to the clinic needs further investigation.

The antimalarial artemisinin is a non-electrophilic agonist of the transient receptor potential ankyrin type 1 receptor-channel.

Artemisinin and its derivatives are the main therapeutic drugs against Plasmodium protists, the causative agents of malaria. While several putative mechanisms of action have been proposed, the precise molecular targets of these compounds have not been fully elucidated. In addition to their antimalarial properties, artemisinins have been reported to act as anti-tumour agents and certain antinociceptive effects have also been proposed. We investigated the effect of the parent compound, artemisinin, on a number of temperature-gated Transient Receptor Potential ion channels (so called thermoTRPs), given their demonstrated roles in pain-sensing and cancer. We report that artemisinin acts as an agonist of the Transient Receptor Potential Ankyrin type 1 (TRPA1) receptor channel. Artemisinin was able to evoke calcium transients in HEK293T cells expressing recombinant human TRPA1, as well as in a subpopulation of mouse dorsal root ganglion (DRG) neurons which also responded to the selective TRPA1 agonist allyl isothiocyanate (AITC) and these responses were reversibly abolished by the selective TRPA1 antagonist A967079. Artemisinin also triggered whole-cell currents in HEK293T cells transiently transfected with human TRPA1, as well as in TRPA1-expressing DRG neurons, and these currents were inhibited by A967079. Interestingly, using human TRPA1 mutants, we demonstrate that artemisinin acts as a non-electrophilic agonist of TRPA1, activating the channel in a similar manner to carvacrol and menthol. These results may provide a better understanding of the biological actions of the very important antimalarial and anti-tumour agent artemisinin.

Should oncologists trust cannabinoids?

Cannabis enjoyed a "golden age" as a medicinal product in the late 19th, early 20th century, but the increased risk of overdose and abuse led to its criminalization. However, the 21st century have witnessed a resurgence of interest and a large body of literature regarding the benefits of cannabinoids have emerged. As legalization and decriminalization have spread around the world, cancer patients are increasingly interested in the potential utility of cannabinoids. Although eager to discuss cannabis use with their oncologist, patients often find them to be reluctant, mainly because clinicians are still not convinced by the existing evidence-based data to guide their treatment plans. Physicians should prescribe cannabis only if a careful explanation can be provided and follow up response evaluation ensured, making it mandatory for them to be up to date with the positive and also negative aspects of the cannabis in the case of cancer patients. Consequently, this article aims to bring some clarifications to clinicians regarding the sometimes-confusing various nomenclature under which this plant is mentioned, current legislation and the existing evidence (both preclinical and clinical) for the utility of cannabinoids in cancer patients, for either palliation of the associated symptoms or even the potential antitumor effects that cannabinoids may have.

Real Check RIO: A Real-World Analysis of Nivolumab in First Line Metastatic Melanoma Assessing Efficacy, Safety and Predictive Factors.

We performed a retrospective study on 51 metastatic melanoma patients treated with Nivolumab in first line, at the Regional Institute of Oncology (RIO) Iasi, Romania between April 2017 and December 2019. We studied the efficacy and safety of anti-PD-1 immune checkpoint inhibitor therapy on a treatment-naive population. After a median follow-up of 36 months, the median progression free survival (PFS) was 26 months (95% CI, 15-36) and the median overall survival (OS) was 31 months (95% CI, 20.1-41.8). At 12 months after the initiation of immunotherapy, the percentage of patients alive was 70%, and at 24 months 62.5%. The most common adverse events observed were dermatological (23.5%) and grade ≥3 was identified in 4 (6.8%) patients. Multivariate analysis indicated that the presence of liver metastases (HR 4.42; 95% CI: 1.88-10.4, p = 0.001) and a neutrophils/lymphocytes ratio (NLR) were associated with poor survival (HR 3.21; 95% CI: 1.04-9.87, p = 0.04). Although retrospective data on a small group of patients were analyzed, we can conclude that our results in RIO are similar to those described in clinical trials and other real-world studies. Our study highlights the potential usefulness of liver metastases and NLR as novel predictive factors in clinical decision-making.

The Impact of Heart Rate Variability Monitoring on Preventing Severe Cardiovascular Events.

The increase in the incidence of cardiovascular diseases worldwide raises concerns about the urgent need to increase definite measures for the self-determination of different parameters, especially those defining cardiac function. Heart rate variability (HRV) is a non-invasive method used to evaluate autonomic nervous system modulation on the cardiac sinus node, thus describing the oscillations between consecutive electrocardiogram R-R intervals. These fluctuations are undetectable except when using specialized devices, with ECG Holter monitoring considered the gold standard. HRV is considered an independent biomarker for measuring cardiovascular risk and for screening the occurrence of both acute and chronic heart diseases. Also, it can be an important predictive factor of frailty or neurocognitive disorders, like anxiety and depression. An increased HRV is correlated with rest, exercise, and good recovery, while a decreased HRV is an effect of stress or illness. Until now, ECG Holter monitoring has been considered the gold standard for determining HRV, but the recent decade has led to an accelerated development of technology using numerous devices that were created specifically for the pre-hospital self-monitoring of health statuses. The new generation of devices is based on the use of photoplethysmography, which involves the determination of blood changes at the level of blood vessels. These devices provide additional information about heart rate (HR), blood pressure (BP), peripheral oxygen saturation (SpO2), step counting, physical activity, and sleep monitoring. The most common devices that have this technique are smartwatches (used on a large scale) and chest strap monitors. Therefore, the use of technology and the self-monitoring of heart rate and heart rate variability can be an important first step in screening cardiovascular pathology and reducing the pressure on medical services in a hospital. The use of telemedicine can be an alternative, especially among elderly patients who are associated with walking disorders, frailty, or neurocognitive disorders.

Breast Sarcomas-How Different Are They from Breast Carcinomas? Clinical, Pathological, Imaging and Treatment Insights.

Breast sarcoma (BS) is a very rare and poorly studied condition. This has led to a lack of studies with a high level of evidence and to low efficacy of current clinical management protocols. Here we present our experience in treating this disease in the form of a retrospective case series study including discussion of clinical, imaging, and pathological features and treatment. We also compare the main clinical and biological features of six cases of BS (phyllodes tumors were excluded) with a cohort of 184 patients with unilateral breast carcinoma (BC) from a previous study performed at our institution. Patients with BS were diagnosed at a younger age, presented no evidence of lymph node invasion or distant metastases, had no multiple or bilateral lesions, and underwent a shorter length of hospital stay versus the breast carcinoma group. Where recommended, adjuvant chemotherapy consisted of an anthracycline-containing regimen, and adjuvant external radiotherapy was delivered in doses of 50 Gy. The comparison data obtained from our BS cases and the ones with BC revealed differences in diagnosis and treatment. A correct pathological diagnosis of breast sarcoma is essential for the right therapeutic approach. We still have more to learn about this entity, but our case series could add value to existing knowledge in a meta-analysis study.

Preventing Dementia-A Cross-Sectional Study of Outpatients in a Tertiary Internal Medicine Department.

Dementia is a significant health problem worldwide, being the seventh leading cause of death (2,382,000 deaths worldwide in 2016). Recent data suggest there are several modifiable risk factors that, if addressed, can decrease dementia risk. Several national dementia screening programs exist; however, limited-income countries do not have the means to implement such measures. We performed a prospective cross-sectional study in an outpatient department to identify individuals at risk for dementia. Patients with no known cognitive dysfunction seeking a medical consult were screened for dementia risk by means of the cardiovascular risk factors, ageing, and dementia (CAIDE) and modified CAIDE tests. Additionally, we collected demographic and clinical data and assessed each participant for depression, mental state, and ability to perform daily activities. Of the 169 patients enrolled, 63.3% were identified as being in the intermediate-risk or high-risk group, scoring more than seven points on the mCAIDE test. Over 40% of the elderly individuals in the study were assessed as "somewhat depressed" or "depressed" on the geriatric depression scale. Almost 10% of the study population was diagnosed de novo with cognitive dysfunction. In conclusion, using a simple questionnaire such as the mCAIDE in a predefined high-risk population is easy and does not represent a major financial burden. At-risk individuals can subsequently benefit from personalized interventions that are more likely to be successful. Limited-resource countries can implement such screening tools in outpatient clinics.

Immune senescence in non-small cell lung cancer management: therapeutic relevance, biomarkers, and mitigating approaches.

INTRODUCTION: Lung cancer and mainly non-small cell lung cancer (NSCLC) still remain a prevalent malignancy worldwide despite sustained screening approaches. Furthermore, a significant proportion of the cases are diagnosed at advanced stages when conservative therapy is often unsuccessful. Cell senescence is an endogenous antitumor weapon but when it is upregulated exerts opposite activities favoring tumor metastasizing and poor response to therapy. However, little is known about this dangerous relationship between cell senescence and NSCLC outcome or on potential approaches to mitigate its unfavorable consequences. AREAS COVERED: We discuss cell senescence focusing on immune senescence, its cell and humoral effectors (namely immune senescence associated secretory phenotype-iSASP), its impact on NSCLC outcome, and its biomarkers. Senotherapeutics as mitigating approaches are also considered based on the availability of experimental data pertinent to NSCLC. EXPERT OPINION: Characterization of NSCLC subsets in which immune senescence is a risk factor for poor prognosis and poor therapeutic response might be very helpful in supporting the addition of senotherapeutics to conventional cancer therapy. This approach has the potential to improve disease outcome but more studies in this area are necessary.

Antiangiogenic Drug-Induced Proteinuria as a Prognostic Factor in Metastatic Colorectal Cancer.

Treatment with bevacizumab is known to cause adverse events such as proteinuria and hypertension, amongst others. However, while bevacizumab-induced hypertension has been linked to increased overall survival (OS), data on proteinuria are controversial. We performed a retrospective analysis to observe the influence of adverse events developed during treatment with bevacizumab and chemotherapy on the OS in patients with metastatic colorectal cancer (mCRC). Kaplan-Meier and log-rank analyses were used to assess differences in OS, and hazard ratios (HR) were estimated using Cox models. Out of the 3497 mCRC patients admitted to our center between 2014 and 2019, 150 met the criteria for inclusion in our analysis. Out of these, 50.7% experienced proteinuria and had reached a longer OS (40 versus 25 months, p = 0.015) and progression-free survival (15 versus 12 months, p = 0.039). The following groups were identified as having a lower risk of death: patients with proteinuria (HR 0.589; 95% CI 0.402-0.863; p = 0.007), one metastatic site (HR 0.533; 95% CI 0.363-0.783; p = 0.001), and non-metastatic stage at diagnosis (HR 0.459; 95% CI 0.293-0.720; p = 0.001). Patients with anemia and diabetes had an increased risk of death. Proteinuria emerges as a useful prognostic factor in mCRC patients undergoing bevacizumab-based systemic therapy, and it could be easily integrated into the decision-making process, thus allowing physicians to further individualize systemic treatments.