Home-based lifestyle intervention for breast cancer survivors: A surprising improvement in the quality of life during the first year of COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic induced an extraordinary impact on public mental health to a degree not completely understood, especially in vulnerable populations such as breast cancer (BC) survivors. In this study, we described the short- (after 3-month) and long- (after 12-month) term effects of a multidisciplinary home-based lifestyle intervention in Italian women BC survivors during the first year of COVID-19 pandemic. MATERIALS AND METHODS: In total, 30 Italian BC survivors with risk factors for recurrence took part in the ongoing MoviS trial (protocol: NCT04818359). Between January 2020 and January 2021, a 3-month lifestyle intervention based on psychological counseling, nutrition, and exercise was carried out. Participants were asked to fill out psychological questionnaires for the assessment of quality of life (QoL) indicators (European Organization for Research and Treatment of Cancer QoL, EORTC-QLQ-C30) and psychological health measures such as fatigue (Brief Fatigue Inventory, BFI), distress (Distress Thermometer, DT and Psychological Distress Inventory, PDI), cancer-related fatigue (Verbal Rating Scale, VRS), and mood states (Profile of Mood States Questionnaire, POMS). IBM SPSS Statistical Software version 27.0 and R Project for Statistical Computing version 4.2.1 were used to process data. All participants were assessed at four time points: T0 (baseline), T1 (3-month), and follow-up at T2 and T3 (6- and 12-month, respectively) to measure primary (quality of life indicators) and secondary (psychological health) outcomes. Friedman non parametric test and Wilcoxon signed rank test (with Bonferroni correction) were conducted to investigate the statistically significant differences in psychometric scores and between assessment times. RESULTS: Compared to baseline (T0), at T1 most of the QoL indicators (i.e., symptoms of fatigue and general health) were improved (p < 0.017) with the exception of a worsening in participants' social functioning ability. Also, perception of severity of fatigue, distress, cancer-related fatigue, depression, and anger enhanced. Compared to baseline (T0), at T3 we mainly observed a stable condition with T0-T1 pairwise comparison, however other secondary outcomes (i.e., fatigue mood state, confusion, and anxiety) significantly improved. DISCUSSION: Our preliminary findings support the proposal of this lifestyle intervention for BC survivors. Despite the home-confinement due to the COVID-19 pandemic, the intervention surprisingly improved QoL indicators and psychological health of the participants.

Effect of a lifestyle intervention program's on breast cancer survivors' cardiometabolic health: Two-year follow-up.

The purpose of this study is to assess the cardiometabolic responses of a lifestyle intervention (LI) conducted at home among breast cancer (BC) survivors during the two years of COVID-19 pandemic. A 3-month LI focused on diet and exercise was performed on thirty BC survivors (women; stages 0-II; non-metastatic; aged 53.6 ± 7.6 years; non-physically active) with a risk factor related to metabolic/endocrine diseases. Anthropometrics, cardiorespiratory fitness (V˙O2max), physical activity level (PAL), adherence to the Mediterranean diet (MeDiet modified questionnaire), and several biomarkers (i.e., glycemia, insulin, insulin resistance [HOMA-IR] index, triglycerides, high- [HDL] and low- [LDL] density lipoproteins, total cholesterol, progesterone, testosterone, and hs-troponin) were evaluated before and 3-, 6-, 12-, and 24-month after the LI. Beneficial effects of the LI were observed on several variables (i.e., body mass index, waist circumference, MeDiet, PAL, V˙ O2max, glycemia, insulin, HOMA-IR index, LDL, total cholesterol, triglycerides, testosterone) after 3-month. The significant effect on Mediterranean diet adherence and V˙ O2max persisted up to the 24-month follow-up. Decreases in HOMA-IR index and triglycerides were observed up to 12-month, however did not persist afterward. This study provides evidence on the positive association between LI and cardiometabolic health in BC survivors.

KRAS4A and KRAS4B in liquid biopsy of metastatic lung adenocarcinoma patients treated with Pembrolizumab or chemotherapy plus Pembrolizumab.

KRAS is involved in the stability and expression of PD-L1. We investigated the expression of circulating mRNA (cmRNA) of KRAS4A and KRAS4B and the possible impact on progression-free survival (PFS) of patients with metastatic lung adenocarcinoma treated with immunotherapy. Patients without driver mutations undergoing Pembrolizumab (P) or P plus chemotherapy (PC) were prospectively accrued for liquid biopsy analysis of KRAS4A, KRAS4B, and PD-L1 cmRNA. Both KRAS isoforms were also studied for association with PD-L1 cmRNA. Of 56 patients, 28 received P and 28 PC. Patients with high levels of both KRAS isoforms showed significantly better PFS. The median PFS for KRAS4A was 29 months (95% CI 22-29 months) and KRAS4B 24 months (95% CI 13-29 months), respectively. The median PFS of patients with low levels of both isoforms was 12 months (95% CI 6-15 months for KRAS4A and 95% CI 5-20 months for KRAS4B). High KRAS4A retained a significant positive association with PFS in the multivariate model. An exploratory analysis in treatment subgroups found a positive association between high KRAS4A and KRAS4B with PFS in patients treated with P. PD-L1 cmRNA was significantly higher in patients with high KRAS isoforms levels and this effect was pronounced for high KRAS4A carriers. KRAS4A deserves further investigation as a potential marker for defining patients who may benefit the most from immune checkpoint inhibitors therapy and improving personalized cancer immunotherapeutic strategies.

Changes in gut microbiota composition after 12 weeks of a home-based lifestyle intervention in breast cancer survivors during the COVID-19 lockdown.

Background: Breast cancer (BC) is the second-leading cause of cancer-related death worldwide. This study aimed to investigate the effects of a 12-week home-based lifestyle intervention (based on nutrition and exercise) on gut microbial composition in twenty BC survivors of the MoviS clinical trial (protocol: NCT04818359). Methods: Gut microbiota analysis through 16S rRNA gene sequencing, anthropometrics, Mediterranean Diet (MD) adherence, and cardiometabolic parameters were evaluated before (Pre) and after (Post) the lifestyle intervention (LI). Results: Beneficial effects of the LI were observed on MD adherence, and cardiometabolic parameters (pre vs post). A robust reduction of Proteobacteria was observed after LI, which is able to reshape the gut microbiota by modulating microorganisms capable of decreasing inflammation and others involved in improving the lipid and glycemic assets of the host. A significant negative correlation between fasting glucose and Clostridia_vadinBB60 (r = -0.62), insulin and homeostatic model assessment (HOMA) index and Butyricicoccus genera (r = -0.72 and -0.66, respectively), and HDL cholesterol and Escherichia/Shigella (r = -0.59) have been reported. Moreover, positive correlations were found between MD adherence and Lachnospiraceae_ND3007 (r = 0.50), Faecalibacterium (r = 0.38) and Butyricimonas (r = 0.39). Conclusion: These data suggest that adopting a healthy lifestyle, may contribute to ameliorate several biological parameters that could be involved in the prevention of cancer relapses through the modulation of gut microbiota.

Impact of Signet-Ring Cell Histology in the Management of Patients with Non-Metastatic Gastric Cancer: Results from a Retrospective Multicenter Analysis Comparing FLOT Perioperative Chemotherapy vs. Surgery Followed by Adjuvant Chemotherapy.

BACKGROUND: FLOT perioperative chemotherapy represents the standard of care in non-metastatic gastric cancer patients. Signet-ring cell positivity is associated with a worse prognosis in patients with gastric cancer treated with chemotherapy. Comparison between FLOT perioperative chemotherapy vs. surgery followed by adjuvant chemotherapy based on signet-ring cell positivity is lacking. The aim of the analysis was to compare perioperative FLOT with adjuvant chemotherapy in gastric cancer patients stratified by signet-ring cell positivity. METHODS: We conducted a retrospective multicenter analysis based on disease-free survival (DFS) and overall survival (OS) in patients with gastric cancer who received perioperative chemotherapy with a FLOT regimen and compared their survival with a historical cohort of patients treated with adjuvant chemotherapy, matched by cT and cN stage and by tumor histological features. RESULTS: Seventy-six patients were enrolled and 24 (32%) were signet-ring cell positive. At a median follow-up time of 39 months, the median DFS was 26.3 months and the median OS was 37.3 months. Signet-ring cell positivity was associated with a shorter OS (median OS: 20.4 vs. 46.9 months, HR: 3.30, 95%CI: 1.56-6.99, p = 0.0018) and DFS (mDFS: 15.2 vs. 38.6 months, HR: 3.18, 95%CI: 1.55-6.54, p = 0.0016). This was confirmed by multivariate analysis for DFS (Exp(B): 2.55) and OS (Exp(B): 2.68). After propensity score matching, statistically significant shorter DFS (HR: 3.30, 95%CI: 1.50-7.35, p = 0.003) and OS (HR: 5.25, 95%CI: 2.18-12-68, p = 0.0002) were observed for patients with signet-ring cell positivity who received perioperative treatment vs. those who received surgery followed by adjuvant chemotherapy. CONCLUSIONS: Signet-ring positivity was associated with shorter DFS and OS in patients who received perioperative treatment with FLOT compared with surgery followed by adjuvant therapy. These data suggest that for patients with signet-ring cell histology, FLOT perioperative treatment might not always be the best choice of treatment, and further research should be focused on this group of patients.

Subjective Perception and Psychoacoustic Aspects of the Laryngectomee Voice: The Impact on Quality of Life.

PURPOSE: A retrospective study is presented to correlate the inter-judge consistency for the different psycho-perceptual parameters of the recently proposed Impression Noise Fluency Voicing (INFVo) perceptual rating scale for substitution voices, and the vocal function as perceived by the patient. METHODS: The scale Voice-Related Quality of Life (V-RQoL) and the Self Evaluation of Communication Experiences After Laryngectomy scale (SECEL)-a self-evaluation questionnaire of communicative experience after laryngectomy surgery-were administered to 89 total laryngectomees, subdivided in four groups depending on their type of alaryngeal voice (i.e., tracheoesophageal and esophageal speakers, electro larynx users, voiceless patients), in order to evaluate the impact of the impairment of the phonatory function on the quality of life. RESULTS: No significant differences exist among the various groups on their perception of QoL using subjective questionnaires, whereas the INFVo scale has proven to be a useful tool for the description and analysis of the psychoacoustic characteristics of the vocal signal and a reliable instrument to correctly classify the patients. It is also notable that the judgement of the patients on their own voice and those of the referees are highly significant. CONCLUSION: Although speech rehabilitation for the acquisition of a substitution voice offers a new way of communication for the laryngectomized patients, nonetheless, their QoL is not significantly related to the type of substitution voice. Therefore, improving the patient's adaptation to the new phonatory condition is mandatory.

Movement and health beyond care, MoviS: study protocol for a randomized clinical trial on nutrition and exercise educational programs for breast cancer survivors.

BACKGROUND: Breast cancer (BC) is the most common invasive cancer in women, and exercise can significantly improve the outcomes of BC survivors. MoviS (Movement and Health Beyond Care) is a randomized controlled trial aimed to evaluate the potential health benefits of exercise and proper nutritional habits. This study aims to assess the efficacy of aerobic exercise training in improving quality of life (QoL) and health-related factors in high-risk BC. METHODS: One hundred seventy-two BC survivor women, aged 30-70 years, non-metastatic, stage 0-III, non-physically active, 6-12 months post-surgery, and post chemo- or radiotherapy, will be recruited in this study. Women will be randomly allocated to the intervention arm (lifestyle recommendations and MoviS Training) or control arm (lifestyle recommendations). The MoviS training consists of 12 weeks of aerobic exercise training (2 days/week of supervised and 1 day/week of unsupervised exercise) with a progressive increase in exercise intensity (40-70% of heart rate reserve) and duration (20-60 min). Both arms will receive counseling on healthy lifestyle habits (nutrition and exercise) based on the World Cancer Research Fund International (WCRF) 2018 guidelines. The primary outcome is the improvement of the QoL. The secondary outcomes are improvement of health-related parameters such as Mediterranean diet adherence, physical activity level, flexibility, muscular fitness, fatigue, cardiorespiratory fitness (estimated maximal oxygen uptake), echocardiographic parameters, heart rate variability (average of the standard deviations of all 5 min normal to normal intervals (ASDNN/5 min) and 24 h very low and low frequency), and metabolic, endocrine, and inflammatory serum biomarkers (glycemia, insulin resistance, progesterone, testosterone, and high-sensitivity C-reactive protein). DISCUSSION: This trial aims to evaluate if supervised exercise may improve QoL and health-related factors of BC survivors with a high risk of recurrence. Findings from this project could provide knowledge improvement in the field of exercise oncology through the participation of a multidisciplinary team that will provide a coordinated program of cancer care to improve healthcare quality, improve prognosis, increase survival times and QoL, and reduce the risk of BC recurrence. TRIAL REGISTRATION: ClinicalTrials.gov  NCT04818359 . Retrospectively registered on March 26, 2021.

Voice rehabilitation and quality of life in laryngectomized patients.

BACKGROUND: Total laryngectomy represents the surgical procedure necessary for the treatment of some advanced neoplasms of the hypopharyngeal-laryngeal district and involves strong functional, physical and emotional repercussions. This research investigated the way in which the rehabilitation methods, used to improve the communicative needs of laryngectomized patients, influence their perceived quality of life. METHOD: The questionnaires "V-RQoL" and "SECEL" were administered to 45 patients divided into four groups on the basis of the type of vicarious voice: group TE (27 patients), group E (7 patients), group EL (2 patients), group NV (9 patients). RESULTS: Patients using electrical or tracheo-esophageal prostheses reported a better quality of life than patients with an erythromophonic voice. Regarding postoperative satisfaction, the group with esophageal voice was the most satisfied. CONCLUSIONS: The results lead us to emphasize the importance of preoperative counseling to make the patient as aware as possible of his future condition. KEY WORDS: Cancer, Laryngectomy, Vicarious Voice, Voice Rehabilitation, Quality of Life.

Effects of a Home-Based Lifestyle Intervention Program on Cardiometabolic Health in Breast Cancer Survivors during the COVID-19 Lockdown.

This study aimed to evaluate the cardiometabolic effects of a home-based lifestyle intervention (LI) in breast cancer survivors (BCSs) during the COVID-19 lockdown. In total, 30 BCSs (women; stages 0-II; non-metastatic; aged 53.5 ± 7.6 years; non-physically active; normal left ventricular systolic function) with a risk factor for recurrence underwent a 3-month LI based on nutrition and exercise. Anthropometrics, Mediterranean diet adherence, physical activity level (PAL), cardiorespiratory fitness (VO2max), echocardiographic parameters, heart rate variability (average standard deviation of NN intervals (ASDNN/5 min) and 24 h very- (24 hVLF) and low-frequency (24 hLF)), and metabolic, endocrine, and inflammatory serum biomarkers (glycemia, insulin resistance, progesterone, testosterone, and high-sensitivity C-reactive protein (hs-CRP)) were evaluated before (T0) and after (T1) the LI. After the LI, there were improvements in: body mass index (kg/m2: T0 = 26.0 ± 5.0, T1 = 25.5 ± 4.7; p = 0.035); diet (Mediet score: T0 = 6.9 ± 2.3, T1 = 8.8 ± 2.2; p < 0.001); PAL (MET-min/week: T0 = 647 ± 547, T1 = 1043 ± 564; p < 0.001); VO2max (mL·min-1·kg-1: T0 = 30.5 ± 5.8, T1 = 33.4 ± 6.8; p < 0.001); signs of diastolic dysfunction (participants: T0 = 15, T1 = 10; p = 0.007); AS-DNN/5 min (ms: T0 = 50.6 ± 14.4, T1 = 55.3 ± 16.7; p = 0.032); 24 hLF (ms2: T0 = 589 ± 391, T1 = 732 ± 542; p = 0.014); glycemia (mg/dL: T0 = 100.8 ± 11.4, T1 = 91.7 ± 11.0; p < 0.001); insulin resistance (HOMA-IR score: T0 = 2.07 ± 1.54, T1 = 1.53 ± 1.11; p = 0.005); testosterone (ng/mL: T0 = 0.34 ± 0.27, T1 = 0.24 ± 0.20; p = 0.003); hs-CRP (mg/L: T0 = 2.18 ± 2.14, T1 = 1.75 ± 1.74; p = 0.027). The other parameters did not change. Despite the home-confinement, LI based on exercise and nutrition improved cardiometabolic health in BCSs.

Metronomic Oral Vinorelbine: An Alternative Schedule in Elderly and Patients PS2 With Local/Advanced and Metastatic NSCLC Not Oncogene-addicted.

BACKGROUND: The MILES and ELVIS studies showed that vinorelbine is one of the best options for elderly patients with advanced non-small-cell-lung cancer (NSCLC). Oral vinorelbine at standard schedule (60-80 mg/m2/weekly) has good activity in terms of response rates and progression-free survival. In recent years, a metronomic schedule of oral vinorelbine (40-50 mg/m2 three times a week, continuously) has been studied in phase II trials, especially in unfit and elderly patients. In the MOVE trial metronomic oral vinorelbine had a clinical benefit [partial response (PR)+stable disease (SD) >12 weeks] in 58.1% of patients with mild toxicity. On this basis, in 2017 we started a phase II study with metronomic oral vinorelbine in elderly (over 70 years) or unfit [Eastern Cooperative Oncology Group performance score (ECOG-PS) of 2] patients with locally/advanced and metastatic NSCLC. Primary aims were clinical benefit (PR+SD ≥6 months) and toxicity; secondary aims were progression-free survival and overall survival. PATIENTS AND METHODS: A total of 25 patients entered the study: 11 with local/advanced and 14 with metastatic NSCLC (five squamous and 20 adenocarcinoma). None of the patients had epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocation, or programmed death ligand 1 (PDL1) expression; those with squamous carcinoma did not have PDL1 expression. The median age was 79 (range=44-90) years. The PS was 0 in 12 patients (48%), 1 in four patients (16%) and 2 in nine patients (36%). Oral vinorelbine was administered at 40 mg three times a week continuously. RESULTS: Clinical benefit was achieved in eight patients (32%). Objective responses were partial response in two patients (8%), stable disease in seven (28%), progressive disease in nine (36%); seven patients were not evaluable for response (28%). Median progression-free survival was 2 months; median overall survival was 4 months but four out of eight patients with clinical benefit were still alive at 18 months. Overall survival at 1 year was 32%. Toxicity was mild: only one patient experienced grade 4 neutropenia, one grade 3 peripheral neuropathy, four grade 2 asthenia, one grade 2 mucositis, and one grade 2 diarrhoea. The dose needed to be reduced to 30 mg/m2/three times a week in three patients. CONCLUSION: Our study confirmed the activity and safety of metronomic oral vinorelbine in patients with wild-type local/advanced and metastatic NSCLC unsuitable for treatment with standard i.v. chemotherapy, allowing patients a comfortable home-based therapy, thereby avoiding frequent hospital visits.

TP53 Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy.

Loss of p53 promotes vascular endothelial growth factor (VEGF)-A up-regulation and the angiogenic potential of cancer cells. We investigated TP53 somatic mutations in 110 primary gastric adenocarcinomas of two retrospective metastatic series including 48 patients treated with second-line Ramucirumab/Paclitaxel and 62 patients who received first-line chemotherapy with Cisplatin or Oxaliplatin plus 5-Fluorouracil. Missense mutations were classified by tumor protein p53 (TP53) mutant-specific residual transcriptional activity scores (TP53RTAS) and used to stratify patients into two groups: transcriptionally TP53Active and TP53Inactive. The primary endpoint was overall survival (OS). An additional analysis was addressed to measure VEGF/VEGF receptor 2 (VEGFR2) expression levels in relation to the TP53RTAS. In the Ramucirumab/Paclitaxel group, 29/48 (60.4%) patients had TP53 mutations. Ten patients with TP53Inactive mutations showed better OS than carriers of other TP53 mutations. This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval = 0.17-0.85, p = 0.02). In the chemotherapy group, 41/62 (66%) patients had TP53 mutations, and the 11 carriers of TP53Inactive mutations showed the worst OS (Hazard Ratio = 2.64, 95% confidence interval = 1.17-5.95, p = 0.02). VEGF-A mRNA expression levels were significantly increased in TP53Inactive cases. Further studies are warranted to explore the effect of TP53Inactive mutations in different anti-cancer regimens. This information would lead to new tailored therapy strategies for this lethal disease.

Glycolytic competence in gastric adenocarcinomas negatively impacts survival outcomes of patients treated with salvage paclitaxel-ramucirumab.

INTRODUCTION: For energy production, cancer cells maintain a high rate of glycolysis instead of oxidative phosphorylation converting glucose into lactic acid. This metabolic shift is useful to survive in unfavorable microenvironments. We investigated whether a positive glycolytic profile (PGP) in gastric adenocarcinomas may be associated with unfavorable outcomes under an anticancer systemic therapy, including the anti-angiogenic ramucirumab. MATERIALS AND METHODS: Normal mucosa (NM) and primary tumor (PT) of 40 metastatic gastric adenocarcinomas patients who received second-line paclitaxel-ramucirumab (PR) were analyzed for mRNA expression of the following genes: HK-1, HK-2, PKM-2, LDH-A, and GLUT-1. Patients were categorized with PGP when at least a doubling of mRNA expression (PT vs. NM) in all glycolytic core enzymes (HK-1 or HK-2, PKM-2, LDH-A) was observed. PGP was also related to TP53 mutational status. RESULTS: Mean LDH-A, HK-2, PKM-2 mRNA expression levels were significantly higher in PT compared with NM. 18 patients were classified as PGP, which was associated with significantly worse progression-free and overall survival times. No significant association was observed between PGP and clinical-pathologic features, including TP53 positive mutational status, in 28 samples. CONCLUSIONS: Glycolytic proficiency may negatively affect survival outcomes of metastatic gastric cancer patients treated with PR systemic therapy. TP53 mutational status alone does not seem to explain such a metabolic shift.

Clinical impact of first-line bevacizumab plus chemotherapy in metastatic colorectal cancer of mucinous histology: a multicenter, retrospective analysis on 685 patients.

PURPOSE: In metastatic colorectal cancer (MCRC), mucinous histology has been associated with poor response rate and prognosis. We investigated whether bevacizumab combined with different chemotherapy regimens may have an impact on clinical outcomes of MCRC patients with mucinous histology. METHODS: 685 MCRC patients were classified in mucinous adenocarcinoma (MC) and non-mucinous adenocarcinoma (NMC) and were treated with first-line bevacizumab plus fluoropyrimidine (FP)-based, oxaliplatin (OXA)-based, irinotecan (IRI)-based, or FOLFOXIRI. RESULTS: Ninety-four (13.7%) patients had MC. With a median follow-up of 50 months, MC patients had a median overall survival (OS) of 28.2 months compared with 27.7 months for the NMC group [hazard ratio (HR) = 0.92; 95% confidence interval (CI) 0.70-1.19, P = 0.530]. The overall response rates for MC and NMC were 41.5% (95% CI 31.5-51.4) and 62.4% (95% CI 58.4-66.3), respectively (Chi-square test, P <0.003). After correcting for significant prognostic factors by multivariate Cox regression analysis, age, resection of the primary tumour, and number of metastatic sites were found to be associated with poorer OS, but not mucinous histology. CONCLUSION: Compared with NMC, MCRC patients with mucinous histology treated with bevacizumab plus chemotherapy had comparable OS despite lower overall response rate.

Assessment of Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line chemotherapy in patients with advanced HER-2 negative gastric or gastroesophageal junction cancers: the ARMANI phase III trial.

BACKGROUND: Platinum/fluoropyrimidine regimens are the backbone of first-line chemotherapy for advanced gastric cancer (AGC). However response rates to first line chemotherapy range from 30 to 50% and disease progression occurs after 4-6 cycles. The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only about 40% of AGC pts. are eligible for second-line treatment. METHODS: This is a randomized, open-label, multicenter phase III trial. It aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after 3 months of a first-line with a platinum/fluoropyrimidine regimen (either FOLFOX4, mFOLFOX6 or XELOX). The primary endpoint is to compare Progression-Free Survival (PFS) of patients in ARM A (switch maintenance to ramucirumab and placlitaxel) versus ARM B (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of patients that will receive a second line therapy according to arm treatment, safety, quality of life. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues are planned in order to identify potential biomarkers of primary resistance and prognosis. DISCUSSION: The ARMANI study estimates if patients treated with early swich with ramucirumab plus paclitaxel received benefit when compared to those treated with continuation of first line therapy. The hypothesis is that the early administration of an active, non-cross resistant second-line regimen such as ramucirumab plus paclitaxel may prolong the time in which patients are progression-free, and consequently have a better quality of life. Moreover, this strategy may rescue all those subjects that become ineligible for second-line therapy due to the rapid deterioration of health status after the first disease progression. TRIAL REGISTRATION: ARMANI is registered at ClinicalTrials.gov ( NCT02934464 , October 17, 2016) and EudraCT(2016-001783-12, April 202,016).

Hepatic Arterial Infusion of Polyethylene Glycol Drug-eluting Beads for Primary and Metastatic Liver Cancer Therapy.

BACKGROUND/AIM: Recently, there has been the launch of the new Polyethylene glycol (PEG) drug-eluting beads (LifePearl®) for transarterial chemoembolization. Their innovation is that PEG guarantees more compressibility, elasticity and maximizes beads' suspension time. We applied these beads for hepatic intra-arterial infusion of irinotecan or doxorubicin for the therapy of primary and metastatic liver cancer. PATIENTS AND METHODS: We treated 20 consecutive patients, affected by unresectable primary liver cancer (PLC) or hepatic metastases (refractory to chemotherapy) using chemoembolization with doxorubicin or irinotecan pre-loaded Lifepearls. RESULTS: Tumor response rate was >80% in most patients with 63% of complete and 37% of partial response. We observed no complications during the chemoembolization and no severe general drug-related side-effects. CONCLUSION: Our data suggest that chemoembolization with LifePearl® is efficacious and safe for the treatment of liver cancer as indicated by good tolerability, quality of life and high tumor response.

Locoregional therapy and systemic cetuximab to treat colorectal liver metastases.

AIM: To investigate efficacy and safety of second-line treatment with irinotecan-loaded drug-eluting beads (DEBIRI) and cetuximab (DEBIRITUX) of unresectable colorectal liver metastases. METHODS: Patients with the following characteristics were included in the study: unresectable hepatic metastases from colorectal carcinoma (CRC-LM), progression after first line chemotherapy (any type of chemotherapeutic drug and combination was allowed), second line treatment (mandatory), which included for each patient (unregarding the KRas status) two cycles of DEBIRI (using 100-300 µm beads loaded with irinotecan at a total dose 200 mg) followed by 12 cycles of cetuximab that was administered weekly at a first dose of 400 mg/m(2) and then 250 mg/m(2); good performance status (0-2) and liver functionality (alanine aminotransferase and gamma-glutamyl transferase not exceeding three times the upper limit of normal, total bilirubin not exceeding 2.5 mg/mL). Data were collected retrospectively and included: tumor response (evaluated monthly for 6 mo then every 3 mo), overall response rate (ORR), KRas status, type and intensity of adverse events (G according to the Common Terminology Criteria for Adverse Events v3.0, CTCAE), overall survival (OS) and progression free survival (PFS). RESULTS: Forty consecutive cases of CRC hepatic metastases were included in the study. Median duration of DEBIRITUX was 4.4 mo (range, 4.0-6.5). Sixteen patients (40%) received the planned 2 cycles of DEBIRI and an average of 10 cetuximab cycles. ORR of the whole sample was 50%, in particular 4 patients were complete responders (10%) and 16 (40%) partial responders. The most observed side effects (G2) were: post-embolization syndrome (30%), diarrhea (25%), skin rushes (38%) and asthenia (35%). The retrospective evaluation of KRas status (24 wild type, 16 mutated) showed that the group of patients with wild type KRas had ORR significantly higher than mutant KRas. Median follow-up was 29 mo (8-48 range); median PFS was 9.8 mo and OS was 20.4 mo. Future randomized trials are required in this setting to establish a role for DEBIRITUX compared with systemic chemotherapy. CONCLUSION: DEBIRITUX seems to be efficacious after first line chemotherapy for the treatment of unresectable CRC-LM.

Natural history of malignant bone disease in hepatocellular carcinoma: final results of a multicenter bone metastasis survey.

BACKGROUND: Bone is an uncommon site of metastasis in patients with advanced hepatocellular carcinoma (HCC). Therefore, there are few studies concerning the natural history of bone metastasis in patients with HCC. PATIENTS AND METHODS: Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 211 deceased HCC patients with evidence of bone metastasis were statistically analyzed. RESULTS: The median age was 70 years; 172 patients were male (81.5%). The median overall survival was 19 months. The median time to the onset of bone metastasis was 13 months (22.2% at HCC diagnosis); 64.9% patients had multiple bone metastases. Spine was the most common site of bone metastasis (59.7%). Most of these lesions were osteolytic (82.4%); 88.5% of them were treated with zoledronic acid. At multivariate analysis, only the Child Score was significantly correlated with a shorter time to diagnosis of bone metastases (p = 0.001, HR = 1.819). The median survival from bone metastasis was 7 months. At multivariate analysis, HCC etiology (p = 0.005), ECOG performance status (p = 0.002) and treatment with bisphosphonate (p = 0.024) were associated with shorter survival after bone disease occurrence. The site of bone metastasis but not the number of bone lesions was associated with the survival from first skeletal related event (SRE) (p = 0.021) and OS (p = 0.001). CONCLUSIONS: This study provides a significant improvement in the understanding the natural history of skeletal disease in HCC patients. An early and appropriate management of these patients is dramatically needed in order to avoid subsequent worsening of their quality of life.

Genetic modulation of the interleukin 6 (IL-6) system in patients with advanced gastric cancer: a background for an alternative target therapy.

BACKGROUND: IL-6 triggers oncogenic/angiogenic signals and the cytokine-dependent pro-cachexia cascade. The prognostic role of the functional IL-6 (promoter) rs1800795 and the IL-6R (receptor) rs8192284 single nucleotide polymorphisms (SNP) was studied in patients with advanced gastric cancer treated with palliative chemotherapy. METHODS: One-hundred-sixty-one patients were genotyped for rs1800795 and rs8192284 SNPs using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) analysis assay. These results were studied for association with overall survival (OS). RESULTS: In 161 assessable patients, frequencies of rs1800795 G/G, G/C and C/C genotypes were 46%, 42% and 12%, respectively. Frequencies of rs8192284 A/A, A/C and C/C genotypes were 36%, 45% and 19%, respectively. Carriers of the rs1800795 G/G and rs8192284 C/C genotypes showed the worst OS. In the multivariate model, rs1800795 G/G (1.69 hazard ratio; 95% confidence interval 1.18-2.42), and rs8192284 C/C (1.78 hazard ratio; 95% confidence interval 1.12-2.83) confirmed an adverse prognostic impact. CONCLUSIONS: In this population, genetic variants that up-regulate the IL-6 system showed impact on OS. This findings sustain the hypothesis that anti-IL-6 compounds deserve clinical studies as novel therapeutics in the palliative treatment of cancer patients.

Chemoembolization in colorectal liver metastases: the rebirth.

Currently image-guided trans-arterial chemoembolization (TACE) has a significant role in the therapy of patients with hepatocellular carcinoma and liver metastases. This endovascular hepatic-directed therapy offers the dual benefit of true local neoplastic control and reduction of side-effects. As a result, it has been included in the guidelines for primary liver cancer and is often considered as salvage therapy for patients liver metastases from neuroendocrine and chemorefractory colorectal tumors. The development of new embolizing agents, such as DC beads loaded with doxorubicin and irinotecan, permits better standardization and definition of protocols, making the procedures less linked to criteria of different hospitals and personal experiences of interventional radiologists. The understanding that hypoxia induces vessel re-growth will open a new avenue for clinical research and a rebirth for TACE. Chemoembolization followed by target therapy (bevacizumab, aflibercept and regorafenib) could increase quality, duration of responses and better quality of life.

The role of macrophages polarization in predicting prognosis of radically resected gastric cancer patients.

Tumour-associated Macrophages (TAM) present two different polarizations: classical (M1) characterized by immunostimulation activity and tumour suppression; alternative (M2) characterized by tumour promotion and immune suppression. In this retrospective study, we evaluated the correlation between the two forms of TAM with survival time in radically resected gastric cancer patients. A total of 52 chemo- and radio-naive patients were included. Two slides were prepared for each patient and double-stained for CD68/NOS2 (M1) or CD68/CD163 (M2) and five representative high-power fields per slide were evaluated for TAM count. The median value of the two macrophage populations density and the median value of M1/M2 ratio were used as cut-off. Twenty-seven patients with M1 density above-the-median had a significantly higher survival compared to those below the median. Twenty-six patients with M1/M2 ratio above the median showed median OS of 27.2 months compared to 15.5 months of the patients below the median. No association between M2 macrophage density and patient's outcome was found. In multivariate analysis, M1/M2 was a positive independent predictor of survival. The M1 macrophage density and M1/M2 ratio, as confirmed in multivariate analysis, are factors that can help in predicting patients survival time after radical surgery for gastric cancer.