Our goal was to investigate if and how pre-operative inflammatory status can influence the long-term prognosis of patients undergoing lung surgery for cancer.
This prospective observational study ...includes the agreement of all operable patients to the study, who were referred to our department between 1 January 2017 and 30 December 2018. The inflammatory pre-operative status of the patients was investigated by calculating albumin, CPR (c-protein reactive), complete blood count (neutrophils, lymphocytes, platelets, hemoglobin), and some other indexes referring to inflammatory status, namely the HALP amalgamated index, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocytes ratio (NLR), systemic immune-inflammation index (SII), and advanced lung cancer inflammation Index (ALI). The follow-up ended in November 2021. Patient overall survival was assessed using the Kaplan-Meier method. The log-rank test was used to compare survival rates. Variables significantly associated with survival at univariate analysis were entered int Cox multivariate analysis (stepwise mode) to assess their independent character. Hazard ratios and their 95% confidence intervals were calculated. Variables associated with
< 0.05 were considered significative.
: We enrolled 257 patients in our study. The overall survival of the cohort was as follows: 1 year, 96.1%; 3 year, 81.3%; and 4 year, 74.2%. Univariate analysis showed risk factors for overall survival as follows: Thoracoscore ≥ 2 (
= 0.002); histology (
= 0.002); HALP < 32.2 (
= 0.0002); SII ≥ 808.9 (
= 0.0004); ALI < 34.86 (
= 0.0005); NLr ≥ 2.29 (
= 0.01); hemoglobin < 13 g/dl (
= 0.01); PLR ≥ 196.1 (
= 0.005); pN+ (
< 0.0001); pleural invasion (
= 0.0002); and presence of vascular or lymphatic tumor emboli (
= 0.0002). Multivariate Cox analysis (stepwise model) identified Thoracoscore ≥ 2 (
= 0.02); histology, HALP < 32.2 (
= 0.004), and pN (
< 0.0001) as independent predictors of death.
Pre-operative inflammatory status strongly influences long-term prognosis in patients affected by NSCLC and undergoing surgery.
Hepatocellular carcinoma (HCC) represents the third cause of cancer death in men worldwide, and its increasing incidence can be explained by the increasing occurrence of non-alcoholic steatohepatitis ...(NASH). HCC prognosis is poor, as its 5-year overall survival is approximately 18 % and most cases are diagnosed at an inoperable advanced stage. Moreover, tumor sensitivity to conventional chemotherapeutics (particularly to cisplatin-based regimen), trans-arterial chemoembolization (cTACE), tyrosine kinase inhibitors, anti-angiogenic molecules and immune checkpoint inhibitors is limited. Oncogenic signaling pathways, such as HIF-1α and RAS/PI3K/AKT, may provoke drug resistance by enhancing the aerobic glycolysis (“Warburg effect”) in cancer cells. Indeed, this metabolism, which promotes cancer cell development and aggressiveness, also induces extracellular acidity. In turn, this acidity promotes the protonation of drugs, hence abrogating their internalization, since they are most often weakly basic molecules. Consequently, targeting the Warburg effect in these cancer cells (which in turn would reduce the extracellular acidification) could be an effective strategy to increase the delivery of drugs into the tumor. Phosphofructokinase-1 (PFK1) and its activator PFK2 are the main regulators of glycolysis, and they also couple the enhancement of glycolysis to the activation of key signaling cascades and cell cycle progression. Therefore, targeting this “Gordian Knot” in HCC cells would be of crucial importance. Here, we suggest that this could be achieved by citrate administration at high concentration, because citrate is a physiologic inhibitor of PFK1 and PFK2. As shown in various in vitro studies, including HCC cell lines, administration of high concentrations of citrate inhibits PFK1 and PFK2 (and consequently glycolysis), decreases ATP production, counteracts HIF-1α and PI3K/AKT signaling, induces apoptosis, and sensitizes cells to cisplatin treatment. Administration of high concentrations of citrate in animal models (including Ras-driven tumours) has been shown to effectively inhibit cancer growth, reverse cell dedifferentiation, and neutralize intratumor acidity, without apparent toxicity in animal studies. Citrate may also induce a rapid secretion of pro-inflammatory cytokines by macrophages, and it could favour the destruction of cancer stem cells (CSCs) sustaining tumor recurrence. Consequently, this “citrate strategy” could improve the tumor sensitivity to current treatments of HCC by reducing the extracellular acidity, thus enhancing the delivery of chemotherapeutic drugs into the tumor. Therefore, we propose that this strategy should be explored in clinical trials, in particular to enhance cTACE effectiveness.
Normal tissue complication probability (NTCP) models that were formulated in the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) are one of the pillars in support of everyday’s ...clinical radiation oncology. Because of steady therapeutic refinements and the availability of cutting-edge technical solutions, the ceiling of organs-at-risk-sparing has been reached for photon-based intensity modulated radiotherapy (IMRT). The possibility to capture heterogeneity of patients and tissues in the prediction of toxicity is still an unmet need in modern radiation therapy. Potentially, a major step towards a wider therapeutic index could be obtained from refined assessment of radiation-induced morbidity at an individual level. The rising integration of quantitative imaging and machine learning applications into radiation oncology workflow offers an unprecedented opportunity to further explore the biologic interplay underlying the normal tissue response to radiation. Based on these premises, in this review we focused on the current-state-of-the-art on the use of radiomics for the prediction of toxicity in the field of head and neck, lung, breast and prostate radiotherapy.
Introduction: Neoadjuvant radiotherapy is currently used mainly in locally advanced rectal cancer and sarcoma and in a subset of non-small cell lung cancer and esophageal cancer, whereas in other ...diseases it is under investigation. The evaluation of the efficacy of the induction strategy is made possible by performing imaging investigations before and after the neoadjuvant therapy and is usually challenging. In the last decade, texture analysis (TA) has been developed to help the radiologist to quantify and identify the parameters related to tumor heterogeneity, which cannot be appreciated by the naked eye. The aim of this narrative is to review the impact of TA on the prediction of response to neoadjuvant radiotherapy and or chemoradiotherapy. Materials and Methods: Key references were derived from a PubMed query. Hand searching and ClinicalTrials.gov were also used. Results: This paper contains a narrative report and a critical discussion of radiomics approaches in different fields of neoadjuvant radiotherapy, including esophageal cancer, lung cancer, sarcoma, and rectal cancer. Conclusions: Radiomics can shed a light on the setting of neoadjuvant therapies that can be used to tailor subsequent approaches or even to avoid surgery in the future. At the same, these results need to be validated in prospective and multicenter trials.
•Relative OAR motion to pancreatic tumors influences delivered doses to OAR in SBRT.•Modeling geometrical variations aids to understand dosimetric uncertainties in OAR.•Common motion patterns exist ...in the gastrointestinal organs.•Motion is larger in anterior regions, being limited in abdominal cavity closer to tumor.•The model is able to simulate real anatomies, since clinical DVHs were reproduced.
To characterize daily geometrical variations of gastrointestinal organs with respect to pancreatic tumors, through a population-based statistical model.
The study included 131 CT scans from 35 pancreatic cancer patients treated with Stereotactic Body Radiotherapy (SBRT). For each patient, day-to-day anatomical variations of the stomach, the duodenum and the bowel were assessed from the deformation vector fields (DVF) obtained by non-rigidly registering the contours of the fractions to the planning CT scans. For the whole population, day-to-day motion-deformation patterns were abstracted using principal component analysis (PCA) on the set of DVFs mapped on a reference patient. Based on these geometrical variations, anatomies were generated to create population-based dose-volume histograms (DVH) per patient, which were also compared to clinical values.
Through PCA, the most dominant directions of daily deformations were localized in the abdominal organs. Common patterns were found, such as stomach contraction–expansion in the anterior–posterior direction ranging from 5 to 13 mm, and superior-inferior deformations on the bowel from 7 to 14 mm. The duodenum resulted to move laterally, but in a lesser extent (4–8 mm). The population-based DVHs derived from the model mostly included the daily DVHs observed in the clinic (in >90% of the cases).
Anatomical variations influence the delivered doses to healthy organs during SBRT. A motion model was successfully built and explored to extract the larger directions of movement of the gastrointestinal organs. Day-to-day motion modeling can potentially be used to account for geometrical uncertainties in future plan optimization and in online adaptive strategies.
Introduction: Stereotactic body radiotherapy (SBRT) reported excellent outcomes and a good tolerability profile in case of central lung tumors, as long as risk-adapted schedules were adopted. High ...grade toxicity was more frequently observed for tumors directly touching or overlapping the trachea, proximal bronchial tree (PBT), and esophagus. We aim to identify prognostic factors associated with survival for Ultra-Central (UC) tumors. Methods: We retrospectively evaluated patients treated with SBRT for primary or metastatic UC lung tumors. SBRT schedules ranged from 45 to 60 Gy. Results: A total number of 126 ultra-central lung tumors were reviewed. The Median follow-up time was 23 months. Median Overall Survival (OS) and Progression Free Survival (PFS) was 29.3 months and 16 months, respectively. Local Control (LC) rates at 1 and 2 were 86% and 78%, respectively. Female gender, age < 70 years, and tumor size < 5 cm were significantly associated with better OS. The group of patients with tumors close to the trachea but further away from the PBT also correlated with better OS. The acute G2 dysphagia, cough, and dyspnea were 11%, 5%, and 3%, respectively. Acute G3 dyspnea was experienced by one patient. Late G3 toxicity was reported in 4% of patients. Conclusion: risk-adaptive SBRT for ultra-central tumors is safe and effective, even if it remains a high-risk clinical scenario.
Lower pre-surgery Body Mass Index (BMI) and low muscle mass impact negatively long-term survival of non-small cell lung cancer (NSCLC). We investigated their influence on survival after major lung ...resection for NSCLC.
A retrospective analysis of a prospectively collected database was made on 304 consecutive patients.
Underweight, normal, overweight and obese patients represented 7.6%, 51.6%, 28.6%, and 12.6% of the pre-disease population. Weight loss and gain were recorded in 5% and 44.4% of patients, respectively. Low muscle mass was more frequently associated with BMI < 25 kg/m
(
< 0.000001). Overall survival was positively affected by pre-disease (
= 0.036) and pre-surgery (
0.017) BMI > 25 kg/m
, and, even more, in case of BMI > 25 kg/m
and increasing weight (
= 0.012). Long-term outcome was negatively influenced by low muscle mass (
= 0.042) and weight loss (
0.0052) as well as age (
0.017), ASA categories (
0.025), extent of resection (
0.0001), pleural invasion (
0.0012) and higher pathologic stage (
< 0.0001). Three stepwise multivariable models confirmed the independent favorable prognostic value of higher pre-disease (RR 0.660.49-0.89,
0.006) and pre-surgery BMI (RR 0.720.54-0.98,
0.034), and the absence of low muscle mass (RR 0.560.37-0.87,
0.0091).
Body reserves assessed by simple clinical markers impact survival of surgically treated NSCLC. Strategies improving body fat and muscular mass before surgery should be considered.
Highlights • Oral mucositis is a complication of radiotherapy used for head-neck cancer treatment. • Rosiglitazone protects normal tissues from radiation-induced oral mucositis. • Rosiglitazone does ...not protect the tumor from therapeutic effect of irradiation. • Rosiglitazone could be proposed as radioprotective agent in head-neck cancer.
Trabectedin is used for the treatment of advanced soft tissue sarcomas (STSs). In this study, we evaluated if trabectedin could enhance the efficacy of irradiation (IR) by increasing the intrinsic ...cell radiosensitivity and modulating tumor micro-environment in fibrosarcoma (HS 93.T), leiomyosarcoma (HS5.T), liposarcoma (SW872), and rhabdomyosarcoma (RD) cell lines. A significant reduction in cell surviving fraction (SF) following trabectedin + IR compared to IR alone was observed in liposarcoma and leiomyosarcoma (enhancement ratio at 50%, ER50: 1.45 and 2.35, respectively), whereas an additive effect was shown in rhabdomyosarcoma and fibrosarcoma. Invasive cells' fraction significantly decreased following trabectedin ± IR compared to IR alone. Differences in cell cycle distribution were observed in leiomyosarcoma and rhabdomyosarcoma treated with trabectedin + IR. In all STS lines, trabectedin + IR resulted in a significantly higher number of γ-H2AX (histone H2AX) foci 30 min compared to the control, trabectedin, or IR alone. Expression of ATM, RAD50, Ang-2, VEGF, and PD-L1 was not significantly altered following trabectedin + IR. In conclusion, trabectedin radiosensitizes STS cells by affecting SF (particularly in leiomyosarcoma and liposarcoma), invasiveness, cell cycle distribution, and γ-H2AX foci formation. Conversely, no synergistic effect was observed on DNA damage repair, neoangiogenesis, and immune system.
Hepatocellular carcinoma (HCC) is the most frequent liver malignancy and a leading cause of cancer death in the world. In unresectable HCC patients, transcatheter arterial (chemo-) embolization ...(TAE/TACE) has shown a disease response in 15-55% of cases. Though multiple TAE/TACE courses can be administered in principle, Stereotactic Body Radiotherapy (SBRT) has emerged as an alternative option in the case of local relapse following multiple TAE/TACE courses.
This is a single-center, prospective, randomized, controlled, parallel-group superiority trial of SBRT versus standard TAE/TACE for the curative treatment of the intermediate stage of HCC after an incomplete response following TAE/TACE (NCT02323360). The primary endpoint is 1-year local control (LC): 18 events were needed to assess a 45% difference (HR: 0.18) in favor of SBRT. The secondary endpoints are 1-year Progression-Free Survival (PFS), Distant Recurrence-Free Survival (DRFS), Overall Survival (OS) and the incidence of acute and late complications.
At the time of the final analysis, 40 patients were enrolled, 19 (49%) in the TAE/TACE arm and 21 (51%) in the SBRT arm. The trial was prematurely closed due to slow accrual. The 1- and 2-year LC rates were 57% and 36%. The use of SBRT resulted in superior LC as compared to TAE/TACE rechallenge (median not reached versus 8 months,
= 0.0002). PFS was 29% and 16% at 1 and 2 years, respectively. OS was 86% and 62% at 1 year and 2 years, respectively. In the TAE arm, PFS was 13% and 6% at 1 and 2 years, respectively. In the SBRT arm, at 1 and 2 years, PFS was 37% and 21%, respectively. OS at 1 and 2 years was 75% and 64% in the SBRT arm and 95% and 57% in the TACE arm, respectively. No grade >3 toxicity was recorded.
SBRT is an effective treatment option in patients affected by inoperable HCC experiencing an incomplete response following ≥1 cycle of TAE/TAC.
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