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.

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.

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.

Oxidant stress as a major determinant of platelet activation in invasive breast cancer.

The hypothesis that increased oxidative stress in breast cancer (BC) patients could induce enhanced lipid peroxidation, which, in turn, would contribute to platelet activation and poor clinical outcome is attractive. To address this issue, we investigated pre-surgical urinary 8-iso-prostaglandin (PG)F2α (marker of in vivo oxidative stress) and 11-dehydro-thromboxane (TX)B2 (marker of in vivo platelet activation) levels in patients with primary BC (n = 115) compared with control women paired for comorbidities and their association with patients' metabolic profile and clinical prognostic factors. The results obtained showed that presurgical urinary excretion of both biomarkers was enhanced in BC patients compared to controls and was associated with patients' estrogen receptor (ER) expression, but not HER2 status or Ki67 proliferation index. Accordingly, both urinary biomarkers were increased in patients with luminal-like BC molecular subtypes compared with triple negative or HER2-enriched tumors. ER status was an independent predictor of 8-iso-PGF2α urinary levels, which, in turn, significantly predicted 11-dehydro-TXB2 urinary levels together with disease stage and ER status. The prognostic value of 11-dehydro-TXB2 was then evaluated showing a significant correlation with BC pathological response to neoadjuvant treatment. Furthermore, among relapsing patients, those with elevated urinary biomarker levels were more likely to develop distant metastasis rather than local recurrence. In conclusion, we may speculate that enhanced oxidative stress due to estrogen-related mechanisms might cause a condition of persistent platelet activation capable of sustaining BC growth and progression through the release of bioactive stored molecules, ultimately contributing to tumor invasiveness. Further studies specifically addressing this hypothesis are presently needed.

Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression.

BACKGROUND: Based on the hypothesis that impaired glucose metabolism might be associated with survival outcomes independently of overt diabetes, we sought to investigate the prognostic value of routinely used glycemic parameters in a prospective study of breast cancer (BC) patients. PATIENTS AND METHODS: Fasting blood glucose, insulin and HbA1c levels, and insulin resistance (assessed by the Homeostasis Model Assessment [HOMA] index) at diagnosis were evaluated in 286 nondiabetic BC patients (249 with primary cancer, 37 with metastatic) with respect to those parameters' possible associations with clinicopathological features and survival outcomes. As a control group, 143 healthy women matched in a 2:1 ratio for age, blood lipid levels, and body mass index were also investigated. RESULTS: Fasting blood glucose level (mean ± SD: 99 ± 26 vs. 85 ± 15 mg/dL), insulin level (median: 10.0 vs. 6.8 µIU/mL), and HOMA index (median: 2.2 vs. 1.4), but not HbA1c level, were significantly elevated in BC patients compared with control subjects. Receiver operating characteristics analysis showed comparable areas for blood glucose and insulin levels, and HOMA index (ranging from 0.668 to 0.671). Using a cutoff level of 13 µIU/mL, insulin had the best specificity (92%) and sensitivity (41%), was significantly associated with disease stage, and acted as a negative prognostic marker of progression-free survival (hazard ratio: 2.17; 95% confidence interval: 1.13-4.20) independently of menopausal status, disease stage, hormone receptor status, and human epidermal growth factor receptor 2 and Ki67 expression. CONCLUSION: These results suggest that insulin determination might provide prognostic information in BC and support the hypothesis that lifestyle and/or pharmacological interventions targeting glucose metabolism could be considered to improve survival outcome of selected BC patients. IMPLICATIONS FOR PRACTICE: Pretreatment insulin levels may represent a biomarker of adverse prognosis in nondiabetic women with breast cancer, independently of other well-established prognostic factors (i.e., stage, hormone receptors, HER2/neu, and Ki67). This finding has important implications, because it provides the rationale for lifestyle or insulin-targeting pharmacologic interventions as a means of improving breast cancer outcomes not only in early stages, but also in advanced-stage breast cancer patients with aggressive tumor phenotypes (HER2-negative hormone-resistant, or triple-negative breast cancer), in which treatments are still challenging. The possibility of using insulin as a biomarker to guide insulin-targeted interventions also should be taken into account.

Venous thromboembolism risk prediction in ambulatory cancer patients: clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio.

Neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) ratios might represent a yet unrecognized risk factor for venous thromboembolism (VTE) in cancer out-patients receiving chemotherapy. Accordingly, this study was aimed at analyzing the significance of these novel markers in the risk prediction of a first VTE episode in a population representative of a general practice cohort. To this purpose, a mono-institutional cohort study was conducted to retrospectively analyze NLR and PLR in 810 consecutive cancer out-patients with primary or relapsing solid cancer at the start of a new chemotherapy regimen. Over a median follow-up of 9.2 months, VTE occurred in 6.7% of patients. Incidental VTE was diagnosed at time of restaging in 47% of cases. Median pre-chemotherapy NLR (p = 0.015) and PLR (p = 0.040) were significantly higher in patients with intermediate risk class who developed symptomatic VTE with a twofold increased VTE risk for both inflammation-based markers (NLR: p = 0.022; PLR: p = 0.037) and a worst 1-year VTE-free survival for patients with high NLR or PLR. However, only PLR (HR = 2.4, p = 0.027) confirmed to be an independent predictor of future VTE in patients in the intermediate risk class in multivariate analysis, together with ECOG performance status (HR = 3.4, p = 0.0002) and bevacizumab use (HR = 4.7, p = 0.012). We may, thus, conclude that PLR, but to a lesser extent NLR, could represent useful clinical predictors of VTE, especially in selected categories of patients such as those in the intermediate risk class in whom the assessment of PLR could allow a better risk stratification of VTE without additional costs to the national health systems.

Estimated glomerular filtration rate is an easy predictor of venous thromboembolism in cancer patients undergoing platinum-based chemotherapy.

Reduced estimated glomerular filtration rate (eGFR) has been associated with increased venous thromboembolism (VTE) risk in the general population. VTE incidence significantly increases in cancer patients, especially those undergoing chemotherapy. Despite the evidence that a substantial number of cancer patients have unrecognized renal impairment, as indicated by reduced eGFR in the presence of serum creatinine levels within the reference value, chemotherapy dosage is routinely adjusted for serum creatinine values. Among chemotherapies, platinum-based regimens are associated with the highest rates of VTE. A cohort study was designed to assess the value of pretreatment eGFR in the risk prediction of a first VTE episode in cancer outpatients without previous history of VTE who were scheduled for platinum-based chemotherapy. Methods. Serum creatinine and eGFR were evaluated before the start of standard platinum-based chemotherapy in a cohort of 322 consecutive patients with primary or relapsing/recurrent solid cancers, representative of a general practice population. Results. Patients who experienced a first VTE episode in the course of chemotherapy had lower mean eGFR values compared with patients who remained VTE free. Multivariate Cox analysis demonstrated that eGFR had an independent value for risk prediction of a first VTE episode during treatment, with a 3.15 hazard ratio. Indeed, 14% of patients with reduced eGFR had VTE over 1-year follow-up compared with 6% of patients with normal eGFR values. Conclusion. The results suggest that reductions in eGFR, even in the presence of normal serum creatinine, are associated with an increased VTE risk in cancer outpatients undergoing platinum-based chemotherapy regimens. Determining eGFR before chemotherapy could represent a simple predictor of VTE, at no additional cost to health care systems.

Evaluation of mean platelet volume as a predictive marker for cancer-associated venous thromboembolism during chemotherapy.

Mean platelet volume has been proposed as a predictor for venous thromboembolism in cancer. We, therefore, investigated the effects of different anti-cancer drugs on mean platelet volume in order to assess its possible value in the risk prediction of a first thromboembolic episode in cancer outpatients during treatment. Pre-treatment mean platelet volumes were retrospectively evaluated in 589 ambulatory patients at the beginning of a new chemotherapy regimen. Moreover, serial changes were evaluated at baseline and before each chemotherapy cycle on 385 of the 589 patients who consented to have additional blood withdrawals during treatment. Cox proportional hazards survival analysis demonstrated a 2.7 hazard ratio (P=0.01) of developing a first venous thromboembolic episode during chemotherapy for patients with baseline mean platelet volumes below the 10(th) percentile (<7.3 fL). This index significantly declined during the first three months of chemotherapy (-6%; P<0.0001) reverting to baseline at the end of treatment. Multivariate regression analysis showed that normal baseline volumes (P=0.012) and platinum-based regimens (P=0.017) were both independent predictors of mean platelet volume decline during chemotherapy which, in turn, was associated with a 2.4 hazard ratio (P=0.044) of venous thromboembolism. In conclusion, low pre-chemotherapy mean platelet volume might be regarded as a predictor of increased venous thromboembolism risk in cancer patients and chemotherapy further decreases platelet volumes, possibly due to drug-induced platelet activation and destruction. Changes in mean platelet volumes during chemotherapy might provide additional information on thromboembolic risk of patients treated with anti-cancer drugs, particularly platinum compounds.

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.

The Use of Artificial Intelligence in Predicting Chemotherapy-Induced Toxicities in Metastatic Colorectal Cancer: A Data-Driven Approach for Personalized Oncology.

BACKGROUND: Machine learning models learn about general behavior from data by finding the relationships between features. Our purpose was to develop a predictive model to identify and predict which subset of colorectal cancer patients are more likely to experience chemotherapy-induced toxicity and to determine the specific attributes that influence the presence of treatment-related side effects. METHODS: The predictor was general toxicity, and for the construction of our data training, we selected 95 characteristics that represent the health state of 74 patients prior to their first round of chemotherapy. After the data were processed, Random Forest models were trained to offer an optimal balance between accuracy and interpretability. RESULTS: We constructed a machine learning predictor with an emphasis on assessing the importance of numerical and categorical variables in relation to toxicity. CONCLUSIONS: The incorporation of artificial intelligence in personalizing colorectal cancer management by anticipating and overseeing toxicities more effectively illustrates a pivotal shift towards more personalized and precise medical care.

Impact of chemotherapy on activated protein C-dependent thrombin generation--association with VTE occurrence.

Chemotherapy has been associated with an increased risk of venous thromboembolism (VTE). However, the prevalence of coagulation abnormalities or VTE occurrence as a consequence of different anti-cancer agents or treatment schemes is largely uncharacterized. Thus, this study was aimed at analyzing the impact of different anticancer drugs on the prothrombotic status of cancer out-patients scheduled for chemotherapy. To this purpose, a mono-institutional study was prospectively conducted to monitor serial changes of activated protein C (APC) function in 505 consecutive cancer out-patients with primary or relapsing solid cancer at the start of a new chemotherapy regimen. The results obtained showed that age >65 years (p = 0.01), ECOG performance status (p = 0.01), platinum-based (p = 0.035) and fluoropyrimidine-based regimens (p = 0.008) were independent predictors of an acquired APC resistance during the first chemotherapy cycle. Multivariate model of Cox proportional hazards survival analysis demonstrated that a decline in APC functionality (HR = 2.4; p = 0.013) and platinum-based regimens (HR = 2.2; p = 0.042) were both capable of predicting the occurrence of a first VTE episode during chemotherapy. Indeed, 14% of patients with platinum-associated APC impairment had VTE over a 1-year follow-up, compared to 3% of patients treated with other regimens and in whom APC functionality remained stable (HR = 1.5; p = 0.003). We may, thus, conclude that use of platinum-based regimens is responsible for induction of an acquired thrombophilic condition and represents a predictor for VTE even after adjustment for other risk factors.

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.

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.

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.

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.

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.

Association between increased tumor necrosis factor alpha levels and acquired activated protein C resistance in patients with metastatic colorectal cancer.

PURPOSE: The purpose of this study was to investigate the possible association between tumor necrosis factor-α (TNF-α) levels and defects in the activated protein C (APC) system as a determinant of venous thromboembolism (VTE) in metastatic colorectal cancer patients (mCRC) undergoing chemotherapy. METHODS: TNF-α levels (measured by immunoassay) and abnormalities in the APC system [evaluated by an APC-dependent thrombin generation assay (ThromboPath-ThP)] were evaluated in 45 mCRC patients undergoing chemotherapy. VTE events were recorded during follow-up. RESULTS: TNF-α levels were increased (p < 0.01), and APC functionality was decreased (p < 0.0001) in mCRC patients compared to age- and sex-matched controls. An inverse correlation was observed between TNF-α and APC impairment in mCRC (p < 0.0001). TNF-α was confirmed as an independent predictor (p = 0.007) for APC abnormalities at multivariate regression analysis. Nine (20 %) of 45 mCRC patients experienced VTE during chemotherapy. Bayesian analysis of combined ThP/TNF-α showed a positive predictive value of 0.67 in predicting VTE (p = 0.01). Cox proportional hazards survival analysis confirmed the predictive value of combined ThP/TNF-α determination in VTE risk assessment of mCRC patients (either negative vs. both positive: HR = 0.02; p = 0.001), and Kaplan-Meier analysis demonstrated that mCRC patients with either negative TNF-α or ThP values prior to chemotherapy were less likely to experience VTE (13 %) than patients with abnormalities of both markers (67 %, p = 0.002). CONCLUSIONS: These results suggest that the host inflammatory response to cancer cells and/or tumor-derived cytokines could be responsible for an impairment of the APC system and a switch toward a pro-thrombotic state, which might predispose to the occurrence of VTE in mCRC patients undergoing chemotherapy.

Early changes of a novel APC-dependent thrombin generation assay during chemotherapy independently predict venous thromboembolism in cancer patients--a pilot study.

PURPOSE: Identifying cancer patients who are most at risk for venous thromboembolism (VTE) is essential to improve timely delivery of chemotherapy. Several studies have been performed to identify novel candidate biomarkers, but no agreement has yet been reached. In this light, we sought to analyze whether a dynamic evaluation of early changes of activated protein C (APC) function during chemotherapy could be predictive of a first VTE episode in cancer outpatients, thus improving risk stratification. METHODS: A retrospective single-center pilot study was conducted to investigate the adequacy of a dynamic evaluation of a novel APC-dependent thrombin generation assay (HemosIL ThromboPath (ThP)) in predicting VTE in 208 ambulatory cancer patients, enrolled on the basis of tight inclusion criteria, prior to start and before the second cycle of a new chemotherapy regimen. RESULTS: Retrospective analysis of samples showed the occurrence of an acquired APC resistance during chemotherapy, which was predictive of VTE. Univariate Cox proportional hazards survival analysis showed that early ThP changes predicted VTE (stable vs. decreasing ThP: hazard ratio (HR) 0.21; 95% CI 0.10-0.19; p < 0.0001), which was confirmed in the multivariate model (HR 0.25; CI 0.12-0.52, p < 0.0001). Stratification of patients according to a risk assessment model showed a 0.18 HR for stable vs. decreasing ThP assay results in an intermediate risk group. CONCLUSIONS: We may thus conclude that early changes of ThP assay in patients on active chemotherapy enhance VTE risk stratification, helping in identifying a population of cancer patients who might benefit from thromboprophylaxis.

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.