Effectiveness of Immunotherapy in Non-Small Cell Lung Cancer Patients with a Diagnosis of COPD: Is This a Hidden Prognosticator for Survival and a Risk Factor for Immune-Related Adverse Events?

The interplay between the immune system and chronic obstructive pulmonary disease (COPD) and non-small cell lung cancer (NSCLC) is complex and multifaceted. In COPD, chronic inflammation and oxidative stress can lead to immune dysfunction that can exacerbate lung damage, further worsening the respiratory symptoms. In NSCLC, immune cells can recognise and attack the cancer cells, which, however, can evade or suppress the immune response by various mechanisms, such as expressing immune checkpoint proteins or secreting immunosuppressive cytokines, thus creating an immunosuppressive tumour microenvironment that promotes cancer progression and metastasis. The interaction between COPD and NSCLC further complicates the immune response. In patients with both diseases, COPD can impair the immune response against cancer cells by reducing or suppressing the activity of immune cells, or altering their cytokine profile. Moreover, anti-cancer treatments can also affect the immune system and worsen COPD symptoms by causing lung inflammation and fibrosis. Immunotherapy itself can also cause immune-related adverse events that could worsen the respiratory symptoms in patients with COPD-compromised lungs. In the present review, we tried to understand the interplay between the two pathologies and how the efficacy of immunotherapy in NSCLC patients with COPD is affected in these patients.

Untailored vs. Gender- and Body-Mass-Index-Tailored Skeletal Muscle Mass Index (SMI) to Assess Sarcopenia in Advanced Head and Neck Squamous Cell Carcinoma (HNSCC).

(1) Background: Sarcopenia lasting >1 year might be considered a chronic condition in many HNSCC patients. CT-scan-derived Skeletal Muscle Mass Index (SMI) is an established surrogate of sarcopenia; yet, the cut-off reported in the literature (literature-based, lb-SMI < 43.2) is mainly based on the risk of chemoradiotherapy-induced toxicity, and the optimal value to discriminate OS is under-investigated. (2) Methods: The effect on OS of the lb-SMI cutoff was compared with an untailored OS-oriented SMI cutoff obtained in a cohort of consecutive advanced HNSCC patients treated with primary chemoradiotherapy, bio-chemotherapy or chemo-immunotherapy (cohort-specific, cs-SMI cutoff). Gender- and BMI-tailored (gt-SMI and bt-SMI) cut-offs were also evaluated. Cutoff values were identified by using the maximally selected rank statistics for OS. (3) Results: In 115 HNSCC patients, the cs-SMI cutoff was 31.50, which was lower compared to the lb-SMI reported cut-off. The optimal cut-off separately determined in females, males, overweight and non-overweight patients were 46.02, 34.37, 27.32 and 34.73, respectively. gt-SMI categorization had the highest effect on survival (p < 0.0001); its prognostic value was independent of the treatment setting or the primary location and was retained in a multivariate cox-regression analysis for OS including other HNSCC-specific prognostic factors (p = 0.0004). (4) Conclusions: A tailored SMI assessment would improve clinical management of sarcopenia in chemoradiotherapy-, bio-chemotherapy- or chemo-immunotherapy-treated HNSCC patients. Gender-based SMI could be used for prognostication in HNSCC patients.

Antibody-Drug Conjugates for the Treatment of Renal Cancer: A Scoping Review on Current Evidence and Clinical Perspectives.

Antibody-drug conjugates (ADCs) are complex chemical structures composed of a monoclonal antibody, serving as a link to target cells, which is conjugated with a potent cytotoxic drug (i.e., payload) through a chemical linker. Inspired by Paul Ehrlich's concept of the ideal anticancer drug as a "magic bullet", ADCs are also highly specific anticancer agents, as they have been demonstrated to recognize, bind, and neutralize cancer cells, limiting injuries to normal cells. ADCs are among the newest pharmacologic breakthroughs in treating solid and hematologic malignancies. Indeed, in recent years, various ADCs have been approved by the Food and Drug Administration and European Medicines Agency for the treatment of several cancers, resulting in a "practice-changing" approach. However, despite these successes, no ADC is approved for treating patients affected by renal cell carcinoma (RCC). In the present paper, we thoroughly reviewed the current literature and summarized preclinical studies and clinical trials that evaluated the activity and toxicity profile of ADCs in RCC patients. Moreover, we scrutinized the potential causes that, until now, hampered the therapeutical success of ADCs in those patients. Finally, we discussed novel strategies that would improve the development of ADCs and their efficacy in treating RCC patients.

Irinotecan- vs. Oxaliplatin-Based Doublets in KRASG12C-Mutated Metastatic Colorectal Cancer-A Multicentre Propensity-Score-Matched Retrospective Analysis.

BACKGROUND: KRASG12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. METHODS: A multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/- bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment-effect interactions. KRASG12D-mutated patients were analysed as control. RESULTS: One hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. However, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. No difference between treatment groups was observed in the KRASG12D-mutated cohort (N = 153). CONCLUSIONS: First-line irinotecan-based regimens provided better survival results in KRASG12C-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations.

HIF2α, Hepcidin and their crosstalk as tumour-promoting signalling.

Not all aspects of the disruption of iron homeostasis in cancer have been fully elucidated. Iron accumulation in cancer cells is frequent for many solid tumours, and this is often accompanied by the contemporary rise of two key iron regulators, HIF2α and Hepcidin. This scenario is different from what happens under physiological conditions, where Hepcidin parallels systemic iron concentrations while HIF2α levels are inversely associated to Hepcidin. The present review highlights the increasing body of evidence for the pro-tumoral effect of HIF2α and Hepcidin, discusses the possible imbalance in HIF2α, Hepcidin and iron homeostasis during cancer, and explores therapeutic options relying on these pathways as anticancer strategies.

Biospecimen Digital Twins: Moving from a "High Quality" to a "Fit-for-Purpose" Concept in the Era of Omics Sciences.

The growing demand for personalized medicine we are currently witnessing has given rise to more in-depth research in the field of biomarker discovery and, thus, in biological banks that hold the ability to process, collect, store, and distribute "high-quality" biological specimens. However, the notion of "specimen quality" is subject to change with technological advancements. In this perspective, we propose that the notion of sample quality should shift from a broad definition of "high-quality" to a "fit-for-purpose" concept more suitable for precision medicine studies. Digital twins are a digital replica of real entities. These are largely adopted in any digitalized domain and are currently finding applications in biomedicine. The adoption of digital twins for biosamples, proposed in this paper, can provide prompt information about the whole lifecycle of the physical twin (i.e., the biosample) and substantially extend the possible matching criteria between the available samples and the researchers' and physicians' requests. This fine-tuning matching could greatly contribute to improving the "fit-for-purpose" quality, not only for studies based on current needs, but also to improve the identification of the best available samples in future situations, determined by the evolution of technologies and biosciences. Assuming and exploiting a data-science view in our biobank perspective, the more (accurate) data there are available, the more information can be extrapolated from them, the more opportunities there are for matching future, currently unknown, needs. This should be a mandatory principle that the 'time machines' called biobanks should follow.

Obesity and Breast Cancer: Interaction or Interference with the Response to Therapy?

Background: Aromatase inhibitors (AI) are widely used for treating hormone-sensitive breast cancer (BC). Obesity, however, due to aromatase-mediated androgen conversion into estradiol in the peripheral adipose tissue, might impair AI inhibitory capacity. We aimed at identifying a cut-off of body mass index (BMI) with significant prognostic impact, in a cohort of stage I-II BC patients on systemic adjuvant therapy with AI. Methods: we retrospectively evaluated routinely collected baseline parameters. The optimal BMI cut-off affecting disease-free survival (DFS) in AI-treated BC patients was identified through maximally selected rank statistics; non-linear association between BMI and DFS in the AI cohort was assessed by hazard-ratio-smoothed curve analysis using BMI as continuous variable. The impact of the BMI cut-off on survival outcomes was estimated through Kaplan−Meier plots, with log-rank test and hazard ratio estimation comparing patient subgroups. Results: A total of 319 BC patients under adjuvant endocrine therapy and/or adjuvant chemotherapy were included. Curve-fitting analysis showed that for a BMI cut-off >29 in AI-treated BC patients (n = 172), DFS was increasingly deteriorating and that the impact of BMI on 2-year DFS identified a cut-off specific only for the cohort of postmenopausal BC patients under adjuvant therapy with AI. Conclusion: in radically resected hormone-sensitive BC patients undergoing neoadjuvant or adjuvant chemotherapy and treated with AI, obesity represents a risk factor for recurrence, with a significantly reduced 2-year DFS.

NTRK Gene Fusions in Solid Tumors and TRK Inhibitors: A Systematic Review of Case Reports and Case Series.

The approval of larotrectinib and entrectinib for cancer patients harboring an NTRK gene fusion has represented a milestone in the era of "histology-agnostic" drugs. Among the clinical trials that led to the approval of these two drugs, most of the enrolled patients were affected by soft tissue sarcomas, lung, and salivary gland cancer. However, as next-generation sequencing assays are increasingly available in the clinical setting, health care professionals may be able to detect NTRK gene fusions in patients affected by tumor types under or not represented in the clinical trials. To this aim, we systematically reviewed MEDLINE from its inception to 31 August 2022 for case reports and case series on patients with NTRK gene fusion-positive tumors treated with TRK inhibitors. A virtual cohort of 43 patients was created, excluding those enrolled in the above-mentioned clinical trials. Although our results align with those existing in the literature, various cases of central nervous system tumors were registered in our cohort, confirming the benefit of these agents in this subgroup of patients. Large, multi-institutional registries are needed to provide more information about the efficacy of TRK inhibitors in cancer patients affected by tumor types under or not represented in the clinical trials.

Nutritional index for immune-checkpoint inhibitor in patients with metastatic gastro-esophageal junction/gastric cancer.

Background: Nutritional status is strongly associated to prognosis in metastatic gastrooesophageal junction (mGOJ)/gastric cancer (GC) patients. The aim of the present study was to develop an immune-checkpoint inhibitor (ICI)-specific nutritional index (NI). Methods: Ten serum and anthropometric nutritional markers derived from blood tests or CT scans were analyzed at baseline in patients treated with second-line ICI and correlated with overall survival (OS). An ICI-specific NI (the NUTRIICI) was developed with its specificity assessed in an independent group of patients treated with standard second-line chemotherapy. Results: From June 2014 to December 2018, 57 mGOJ/GC patients (14 females, 43 males) with a median(m) age of 61 years (range 29-85) received ICI as second-line therapy (Pembrolizumab n=26, Nivolumab n=16, Avelumab n=15). Among the 10 analyzed variables, Onodera's prognostic NI (PNI) ≤33 and waist-to-hip (WHR) <1 were independent predictors of OS and used to build the NUTRIICI. Patients with both favorable factors (i.e., PNI >33 and WHR ≥1, comparator group) had a mOS of 18.0 vs. 6.7 months of patients with one unfavorable factor (either PNI ≤33 or WHR <1, Hazard Ratio, HR 3.06), vs. 1.3 months of patients with both unfavorable factors (HR 17.56), overall P<0.0001. In the independent group of patients treated with standard chemotherapy NUTRIICI was not associated with prognosis (P=0.57). Conclusions: NUTRIICI is the first ICI-specific NI for mOGJ/GC patients receiving second-line ICI. A validation in larger cohorts is strongly encouraged.

Artificial Intelligence Predictive Models of Response to Cytotoxic Chemotherapy Alone or Combined to Targeted Therapy for Metastatic Colorectal Cancer Patients: A Systematic Review and Meta-Analysis.

Tailored treatments for metastatic colorectal cancer (mCRC) have not yet completely evolved due to the variety in response to drugs. Therefore, artificial intelligence has been recently used to develop prognostic and predictive models of treatment response (either activity/efficacy or toxicity) to aid in clinical decision making. In this systematic review, we have examined the ability of learning methods to predict response to chemotherapy alone or combined with targeted therapy in mCRC patients by targeting specific narrative publications in Medline up to April 2022 to identify appropriate original scientific articles. After the literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. Our results show that all investigations conducted on this field have provided generally promising results in predicting the response to therapy or toxic side-effects. By a meta-analytic approach we found that the overall weighted means of the area under the receiver operating characteristic (ROC) curve (AUC) were 0.90, 95% C.I. 0.80-0.95 and 0.83, 95% C.I. 0.74-0.89 in training and validation sets, respectively, indicating a good classification performance in discriminating response vs. non-response. The calculation of overall HR indicates that learning models have strong ability to predict improved survival. Lastly, the delta-radiomics and the 74 gene signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Specifically, when we evaluated the predictive models with tests reaching 80% sensitivity (SE) and 90% specificity (SP), the delta radiomics showed an SE of 99% and an SP of 94% in the training set and an SE of 85% and SP of 92 in the test set, whereas for the 74 gene signatures the SE was 97.6% and the SP 100% in the training set.

The Role of Histology-Agnostic Drugs in the Treatment of Metastatic Castration-Resistant Prostate Cancer.

Precision medicine has opened up a new era in the development of anti-cancer agents that is focused on identifying biomarkers predictive of treatment response regardless of tumor histology. Since 2017, the Food and Drug Administration has approved six drugs with histology-agnostic indications: pembrolizumab (both for tumors with the mismatch-repair deficiency (dMMR)/high microsatellite instability (MSI-H) phenotype and for those with the high tumor mutational burden (TMB-H) phenotype), dostarlimab (for dMMR tumors), larotrectinib and entrectinib (for tumors harboring neurotrophic tyrosine receptor kinase (NTRK) fusions), and the combination of dabrafenib plus trametinib (for BRAF V600E-mutated tumors). The genomic alterations targeted by these antineoplastic agents are rare in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, only a small number of mCRPC patients were enrolled in the clinical trials that led to the approval of the above-mentioned drugs. Therefore, we critically reviewed the literature on the efficacy of histology-agnostic drugs in mCRPC patients. Although the available evidence derives from retrospective studies and case reports, our results confirmed the efficacy of pembrolizumab in dMMR/MSI-H mCRPC. In contrast, few data are available for dostarlimab, larotrectinib, entrectinib, and dabrafenib-trametinib in this subset of patients. Large, multi-institutional registries aimed at collecting real-world data are needed to better comprehend the role of tissue-agnostic drugs in mCRPC patients.

MiRNAs and circRNAs for the Diagnosis of Anthracycline-Induced Cardiotoxicity in Breast Cancer Patients: A Narrative Review.

Breast cancer (BC) is the most frequent type of female cancer with increasing incidence in recent years. Doxorubicin (DOX) is an important backbone chemotherapy in BC, responsible for cardiotoxicity (CTX) in about 9% of treated women within the first year. Biomarkers of early CTX diagnosis are essential to avoid complicated DOX-related cardiac diseases. Traditional serum biomarkers are either poorly sensitive with transient elevation, and even absent if investigated outside their diagnostic window, or arise only in late-stage CTX. Emerging biomarkers such as non-coding RNA (ncRNA) have been recently investigated in DOX-related CTX. In our review, we revised the role of microRNAs, the most studied type of ncRNA, both in animal and human models, highlighting the interesting but often contrasting results. Moreover, we reviewed a novel class of ncRNA, circular RNA (circRNA), focusing on their modulatory mechanisms also involving microRNAs. MicroRNA and circRNA are players in a wide homeostatic balance with their perturbation representing a possible compensation for DOX damage. Further studies are required to assess the modalities of early detection of their variation in BC patients suffering from heart disease induced by DOX treatment.

Immune Response in Vitamin D Deficient Metastatic Colorectal Cancer Patients: A Player That Should Be Considered for Targeted Vitamin D Supplementation.

Background: Vitamin D deficiency is a poor prognostic factor in metastatic colorectal cancer (mCRC); however, targeted supplementation trials have so far yielded limited results. We investigated clinical-laboratory parameters influencing vitamin D deficiency, with a particular focus on immune response, and the effect on survival. These parameters could help optimize targeted supplementation therapy. Methods: Association of plasma 25-hydroxyvitamin D (25(OH])D) with overall survival (OS) was assessed with the Hazard Ratio Smoothed Curve with Restricted Cubic Splines (HRSC-RCS) and maximally selected rank statistics (MSRS) in mCRC patients who underwent first-line chemotherapy. Several hematobiochemical variables were evaluated as predictors of vitamin D deficiency by means of Least Absolute Shrinkage and Selection Operator (LASSO) analysis. In a patient subset, peripheral lymphocyte subpopulations were also analyzed. Results: One hundred thirty-three mCRC patients were included. The median(m) baseline 25(OH)D was 10.8 ng/mL (range 3−53.4). HRSC-RCS revealed a linear association between 25(OH)D and OS. MSRS found 10 ng/mL as the optimal 25(OH)D cut-off. The median OS for 25(OH)D < 10 (n = 60) vs. > 10 ng/mL (n = 73) was 12.3 and 24.5 months, respectively (p = 0.002). The LASSO analysis identified high neutrophil-to-lymphocyte ratio (NLR > 3.5) as the strongest predictor of vitamin D deficiency (Odds Ratio 3.35, p 0.0009). Moreover, patients with low 25(OH)D levels (< 10 ng/mL) and high NLR (>3.5) had the shortest survival and patients with 25(OH)D >10 ng/mL and NLR <3.5 had the longest: mOS 8.1 and 28.1 months, respectively, HR 3.40 (1.76−6.59), p 0.0004. Besides the significant difference in NLR between 25(OH)D < and > 10 ng/mL patients (mNLR 3.6 vs. 2.9, p 0.03), the lymphocyte subpopulation analysis revealed that vitamin D deficiency was associated with high T- CD4+ (p = 0.04) and low B (p = 0.03) lymphocyte frequency. Conclusions: NLR is a powerful predictor of Vitamin D deficiency and can further help in stratifying prognosis. Vitamin D deficiency was associated with significant variations in peripheral immune cells. We hypothesize that integrated targeted interventions to both vitamin D and immune system would improve the prognosis of mCRC patients.

Activity of ALK Inhibitors in Renal Cancer with ALK Alterations: A Systematic Review.

Renal cell carcinoma (RCC) associated with anaplastic lymphoma kinase (ALK) gene rearrangements (ALK-RCC) is currently considered an "emerging or provisional" tumor entity by the last World Health Organization classification published in 2016. Although several studies assessing ALK-RCC's clinical and histological characteristics have been published in recent years, only a few publications have evaluated the activity of ALK inhibitors (ALK-i) in this subgroup of patients. Considering the well-recognized efficacy of this evolving class of targeted therapies in other ALK-positive tumors, we conducted a systematic review to evaluate the reported activity of ALK-i in the ALK-RCC subtype. MEDLINE was searched from its inception to 7 January 2022 for case reports and case series on adult metastatic ALK-RCC patients treated with ALK-i whose therapeutic outcomes were available. A virtual cohort of ALK-RCC patients was created. Our results showed a favorable activity of first- and second-generation ALK-i in pretreated ALK-RCC patients in terms of either radiological response or performance status improvement. We hope that the present work will prompt the creation of large, multi-institutional clinical trials to confirm these promising early data.

KRAS and BRAF Mutations in Stage II and III Colon Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: KRAS and BRAF mutations are well-established predictive and prognostic factors in metastatic colorectal cancer; however, their impact in the adjuvant setting has not yet been established. METHODS: We performed a meta-analysis of adjuvant phase III trials in patients with stage II and III colon cancer with available data on the impact of KRAS or BRAF mutations on both disease-free survival (DFS) and overall survival (OS). Trials were subgrouped based on whether adjustment for microsatellite instability (MSI) was performed and the subgroup effect was analyzed through a meta-regression. To increase the precision of the estimates, a joint DFS-OS (so-called "multivariate") meta-analysis was performed. All statistical tests were 2-sided. RESULTS: Nine trials were selected (QUASAR 2, PETACC-8, N0147, CALGB-89803, NSABP-C07, NSABP-C08, PETACC-3, QUASAR, MOSAIC) including a total of 10 893 patients. In the primary meta-analysis, KRAS mutation was associated with poor DFS (pooled hazard ratio [HR] = 1.36, 95% confidence interval [CI] = 1.15 to 1.61, P < .001) and OS (pooled HR = 1.27, 95% CI = 1.03 to 1.55, P = .03) and BRAF mutation was also associated with poor DFS (pooled HR = 1.33, 95% CI = 1.00 to 1.78, P = .05) and OS (pooled HR = 1.49, 95% CI = 1.31 to 1.70, P < .001). The effect of the mutations on outcome was enhanced in the MSI-adjusted subgroup for both the KRAS mutation (pooled HR for DFS = 1.43, 95% CI = 1.15 to 1.79, P = .001; and pooled HR for OS = 1.33, 95% CI = 1.03 to 1.71, P = .03) and the BRAF mutation (pooled HR for DFS = 1.59, 95% CI = 1.22 to 2.07, P = .001; and pooled HR for OS = 1.67, 95% CI = 1.37 to 2.04, P < .001). The interaction between BRAF and MSI adjustment was statistically significant for DFS (Pinteraction = .02). This interaction was even more pronounced in the DFS-OS multivariate meta-analysis. CONCLUSIONS: Both KRAS and BRAF mutations were statistically significantly associated with both DFS and OS, with the mutation effect being enhanced by MSI adjustment. Effective adjuvant treatment for microsatellite-stable BRAF or KRAS-mutated colon cancer represents an unmet clinical need, and exploring the use of recently available BRAF and KRAS inhibitors in this setting would be highly desirable.

Irinotecan or Oxaliplatin: Which is the First Move for the Mate?

OBJECTIVES: The aim of the present review is to discuss the potential link between RAS, BRAF and microsatellite instability (MSI) mutational patterns and chemotherapeutic agent efficacy [Irinotecan (IRI) vs. Oxaliplatin (OXA)], and how this can potentially influence the choice of the chemotherapy backbone. METHODS: Following a review of the research literature, all pertinent articles published in the core journals were selected for the study. The inclusion criteria regarded relevant clinical and pre-clinical studies on the topic of interest (Relationship of OXA and IRI to KRAS/BRAF mutations and MSI). RESULTS: Excision repair cross complementation group 1 (ERCC1) expression is inhibited by KRAS mutation, making tumor cells more sensitive to OXA. Results from OPUS, COIN and PRIME trials support that no conclusive data are available for BRAF mutant population because of the small number of patients. Enhanced IRI cytotoxicity to MSI cell lines is due to the participation of some of the mismatch repair (MMR) components in various DNA repair processes and their role in the maintenance of the pro-apoptotic effect of IRI and G2/M cell arrest. CONCLUSION: OXA and IRI are indispensable drugs for mCRC treatment and their selection must be as careful as that of targeted agents. We suggest taking into consideration the interaction between known genomic alterations and OXA and IRI activity to personalize chemotherapy in mCRC patients.

Venous Thromboembolism in Cancer Patients on Simultaneous and Palliative Care.

Simultaneous care represents the ideal integration between early supportive and palliative care in cancer patients under active antineoplastic treatment. Cancer patients require a composite clinical, social and psychological management that can be effective only if care continuity from hospital to home is guaranteed and if such a care takes place early in the course of the disease, combining standard oncology care and palliative care. In these settings, venous thromboembolism (VTE) represents a difficult medical challenge, for the requirement of acute treatments and for the strong impact on anticancer therapies that might be delayed or, even, totally discontinued. Moreover, cancer patients not only display high rates of VTE occurrence/recurrence but are also more prone to bleeding and this forces clinicians to optimize treatment strategies, balancing between hemorrhages and thrombus formation. VTE prevention is, therefore, regarded as a double-edged sword. Indeed, while on one hand the appropriate use of antithrombotic agents can reduce VTE occurrence, on the other it significantly increases the bleeding risk, especially in the frail patients who present with multiple co-morbidities and poly-therapy that can interact with anticoagulant drugs. For these reasons, thromboprophylaxis should start while active cancer treatment is ongoing, according to a simultaneous care model in a patient-centered perspective.

Clinical Utility of Plasma KRAS, NRAS and BRAF Mutational Analysis with Real Time PCR in Metastatic Colorectal Cancer Patients-The Importance of Tissue/Plasma Discordant Cases.

BACKGROUND: Tumor tissue (T) mutational analysis represents the standard for metastatic colorectal cancer (mCRC); however, circulating tumor DNA (ctDNA) detected by liquid biopsy in plasma (PL) can better represent tumor heterogeneity. METHODS: mCRC patients undergoing standard first-line chemotherapy with known T-KRAS/NRAS/BRAF status were enrolled in the present prospective study. PL mutations were assessed within 2 weeks before chemotherapy start with real time PCR and correlated with T status and Progression free survival (PFS). Clinical and biochemical variables including also total number of tumor lesions (TNL) and the sum of maximum diameter (SMD) of all lesions were assessed as potential predictors of T/PL discordance. RESULTS: Among 45 enrolled patients, all BRAF mutations were concordant between T and PL and there were 20% of patients RAS discordant: 9% wild type in T and mutated in PL and 11% mutated in T and wild type in PL. T mutations were significantly associated to median PFS (mPFS of 4.5, 8.3 and 22.9 months for T-BRAF mutated, T-RAS mutated, and T-wild type patients, respectively, p for trend 0.00014). PL mutations further refined prognosis: RAS wild type in T and mutated in PL had significantly shorter PFS than concordant RAS wild type in T and PL: mPFS 9.6 vs. 23.3 months, respectively, p = 0.02. Patients RAS mutated in T and wild type in PL had longer PFS than concordant RAS mutated in T and PL: 24.4 vs. 7.8 months, respectively, p = 0.008. At a multivariate cox regression analysis for PFS, PL mutations were independent prognostic factor superior to T analysis (HR 0.13, p = 0.0008). At multivariate logistic regression analysis TNL and SMD were significant predictors of discordant cases. CONCLUSIONS: PL mutational analysis allows a better prognostication than T analysis alone and could help in mCRC treatment management.