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 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.

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.

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.

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.

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.

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 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.

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.

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.

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 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.

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.

Factors Associated with Burnout in Healthcare Professionals.

Burnout in healthcare professionals remains an ongoing concern. There are a number of variables associated with reactivity to stress in healthcare staff. This study wants to identify risk factors which predispose healthcare professionals to burnout. MATERIAL AND METHODS: The cross-sectional study included a group of 200 subjects, medical staff and auxiliary staff from the national health units, who gave their free consent to answer the questions regarding the level of perceived stress at work. The screening tool used was disseminated through the Google Forms platform, maintaining the anonymity of the participants. RESULTS: Resident doctors (42%) responded predominantly, reporting the highest level of burnout, with nurses (26.5%) being the least affected (χ2 = 36.73, p < 0.01). Less work experience is correlated with increased burnout (rho = 0.29, p < 0.01). Reactivity to stress was highly associated with workplace, with ambulance staff being the most vulnerable (χ2 = 6.58, p < 0.05). Participants' relationship status significantly influenced the burnout rate, the unmarried, with or without a partner, being more affected (χ2 = 16.14, p < 0.01). There are no significant differences between male and female gender, regarding the average level of burnout (U = 1.47; p > 0.05), nor between living in a house or apartment (U = 4.66; p > 0.05). Positive associations were identified between the level of burnout and variables such as: management pressure, administrative work, routine, regretting decisions regarding patients, harassment at work and sacrifice of personal time. CONCLUSIONS: The results of this study identify age, profession, workplace seniority and relationship status as factors associated with burnout in medical personnel.

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.

Can Extended Chemotherapy Improve Glioblastoma Outcomes? A Retrospective Analysis of Survival in Real-World Patients.

Standard treatment for glioblastoma multiforme (GBM) is surgery followed by radiotherapy plus concurrent chemotherapy with daily temozolomide (TMZ), and six subsequent TMZ 5/28-day cycles. Research has focused on identifying more effective alternatives to the current protocol, including extension of the number of adjuvant TMZ cycles. We performed a retrospective analysis of all GBM patients treated in our hospital (160 patients, 2011−2020). Median follow-up was 16.0 months. Analysis of prognostic factors was performed with a particular focus on the benefit of extending TMZ chemotherapy. Improved survival correlated with younger age, female gender, good performance status, absence of cognitive dysfunctions, no steroid use, and total tumor resection. Median progression-free survival (PFS) was 12 months and median overall survival (OS) was 20.0 months for the entire cohort. Median OS by adjuvant TMZ was 10.0 months if no adjuvant chemotherapy given (group 0), 15.0 months for patients that did not complete six TMZ cycles (group A), 24.0 months for those that did (group B), and 29.0 months for patients having received more than six cycles (group C) (p < 0.0001). At the three-year mark, 15.9% patients were alive in group A, 24.4% in group B and 38.1% in group C. Carefully selected GBM patients may derive benefit from extending the standard adjuvant chemotherapy beyond six TMZ cycles, but more data is required.

The Therapeutic Potential of the Endocannabinoid System in Age-Related Diseases.

The endocannabinoid system (ECS) dynamically regulates many aspects of mammalian physiology. ECS has gained substantial interest since growing evidence suggests that it also plays a major role in several pathophysiological conditions due to its ability to modulate various underlying mechanisms. Furthermore, cannabinoids, as components of the cannabinoid system (CS), have proven beneficial effects such as anti-inflammatory, immunomodulatory, neuromodulatory, antioxidative, and cardioprotective effects. In this comprehensive review, we aimed to describe the complex interaction between CS and most common age-related diseases such as neuro-degenerative, oncological, skeletal, and cardiovascular disorders, together with the potential of various cannabinoids to ameliorate the progression of these disorders. Since chronic inflammation is postulated as the pillar of all the above-mentioned medical conditions, we also discuss in this paper the potential of CS to ameliorate aging-associated immune system dysregulation.

Oxaliplatin-induced neuropathy and colo-rectal cancer patient's quality of life: Practical lessons from a prospective cross-sectional, real-world study.

BACKGROUND: Colon cancer is one the most common forms of cancer in both sexes. Due to important progress in the field of early detection and effective treatment, colon and rectal cancer survivors currently account for 10% of cancer survivors worldwide. However, the effects of anti-cancer treatments, especially oxaliplatin-based chemotherapy, on the quality of life (QoL) have been less evaluated. Although the incidence of severe chemotherapy-induced neuropathy (CIPN) in clinical studies is below 20%, data from real-world studies is scarce, and CIPN is probably under-reported due to patient selection and the patients' fear that reporting side-effects might lead to treatment cessation. AIM: To determine the impact of CIPN on QoL in colorectal cancer patients with a recent history of oxaliplatin-based chemotherapy. METHODS: We performed a prospective cross-sectional study in two major Romanian oncology tertiary hospitals-the Regional Institute of Oncology Iași (Iasi, Romania) and the Fundeni Clinical Oncology Institute (Bucharest, Romania). All consecutive patients with colon or rectal cancer, undergoing Oxaliplatin-based chemotherapy that consented to enroll in the study, were assessed by means of two questionnaires-the EORTC QQ-CR29 (quality of life in colon and rectal cancer patients) and the QLQ-CIPN20 (assessment of neuropathy). Several demographical, social, clinical and treatment data were also collected. Statistical analysis was performed by means of SPSS v20. The student t test was used to assess the relationship between the QLQ-CIPN20 and QLQ-CR29 results. Kaplan Meyer-curves were used to report 3-year progression-free survival (PFS) in patients that discontinued chemotherapy vs those that completed the recommended course. RESULTS: Of the 267 patients that fulfilled the inclusion criteria in the pre-specified time frame, 101 (37.8%) agreed to participate in the clinical study. At the time of the enrolment in the study, over 50% of the patients had recently interrupted their oxaliplatin-based chemotherapy, most often due to neuropathy. Almost 85% of the responders reported having tingling or numbness in their fingers or hands, symptoms that were associated with pain in over 20% of the cases. When comparing the scores in the two questionnaires, a statistically significant relationship (P < 0.001) was found between the presence of neuropathic symptoms and a decreased quality of life. This correlation was consistent when the patients were stratified by sex, disease stage, comorbidities and the presence of stoma or treatment type, suggesting that neuropathy in itself may be a reason for a decreased quality of life. At the 3 year final assessment, median recurrence-free survival in stage III patients was 26.88 mo. When stratified by completion of chemotherapy, median recurrence free-survival of stage III patients that completed chemotherapy was 28.27 mo vs 24.33 mo in patients that discontinued chemotherapy due to toxicity, a difference that did not reach statistical significance. CONCLUSION: CIPN significantly impacts QoL in colorectal cancer patients. CIPN is also the most frequent reason for treatment discontinuation. Physicians should actively assess for CIPN in order to prevent chronic neuropathy.

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.

Major Phytocannabinoids and Their Related Compounds: Should We Only Search for Drugs That Act on Cannabinoid Receptors?

The most important discoveries in pharmacology, such as certain classes of analgesics or chemotherapeutics, started from natural extracts which have been found to have effects in traditional medicine. Cannabis, traditionally used in Asia for the treatment of pain, nausea, spasms, sleep, depression, and low appetite, is still a good candidate for the development of new compounds. If initially all attention was directed to the endocannabinoid system, recent studies suggest that many of the clinically proven effects are based on an intrinsic chain of mechanisms that do not necessarily involve only cannabinoid receptors. Recent research has shown that major phytocannabinoids and their derivatives also interact with non-cannabinoid receptors such as vanilloid receptor 1, transient receptor ankyrin 1 potential, peroxisome proliferator-activated receptor-gamma or glitazone receptor, G55 protein-coupled receptor, and nuclear receptor, producing pharmacological effects in diseases such as Alzheimer's, epilepsy, depression, neuropathic pain, cancer, and diabetes. Nonetheless, further studies are needed to elucidate the precise mechanisms of these compounds. Structure modulation of phytocannabinoids, in order to improve pharmacological effects, should not be limited to the exploration of cannabinoid receptors, and it should target other courses of action discovered through recent research.