Circulating tumour cell gene expression and chemosensitivity analyses: predictive accuracy for response to multidisciplinary treatment of patients with unresectable refractory recurrent rectal cancer or unresectable refractory colorectal cancer liver metastases.

BACKGROUND: Patients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs). METHODS: In this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected. RESULTS: Our analyses resulted in evaluations of 94.12% (95% CI 0.71-0.99) for sensitivity, 5.26% (95% CI 0.01-0.26) for specificity, a predictive value of 47.06% (95% CI 0.29-0.65) for a positive response, a predictive value of 50% (95% CI 0.01-0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30-0.64). CONCLUSIONS: This is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials.

The acute impact of an ultramarathon on right heart: A 12-lead ECG study.

BACKGROUND: Some concerns exist about possible detrimental effects on cardiac function of ultra-endurance competitions. The aim of this study was to evaluate the acute effects of an ultramarathon by comparing pre- and post-race 12-lead ECG features. METHODS: A total of 301 competitive athletes (mean age: 48 ± 9 years) running a 50-km ultramarathon were analyzed. Twelve-lead ECG was collected the day before the race and immediately at the finish line. According to the Italian law, athletes could have participated only after undergoing pre-participation screening that ruled out the presence of an underlying heart disease. RESULTS: After the race a significant increase in P-wave voltage (P < .001) and P-wave duration (P < .001) was found as compared to pre-race data with a higher percentage of athletes fulfilling the ECG criteria for right atrial enlargement (RAE; from 3% to 17%, P < .001). The presence of RAE post-race significantly correlated with age, hours of training/week, and years of training and inversely with time at the finish line and the final position in the ranking. T-wave and R-wave amplitude (P < .001) and QTc-interval duration (P < .001) significantly increased after the race. No significant differences in terms of supraventricular or ventricular arrhythmias were found. CONCLUSIONS: A sizeable proportion of athletes running a 50-km ultramarathon demonstrated post-race ECG signs of right heart overload but no arrhythmias. This finding supports the hypothesis that ultra-endurance races may induce transient right heart overload.

A review discussing the use of polyethylene glycol microspheres in the treatment of hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is indicated in unresectable hepatocellular carcinoma and allows the delivery of embolics inside tumor vascularization to reduce blood supply and release gradually the drug. This lowers the systemic exposure to chemotherapeutics, while increasing their local concentration and tissue necrosis that is higher than conventional TACE. The technology of TACE has seen the introduction of several types of embolics that are made of different materials. Available embolics for TACE include: drug-eluting beads (DC beads), acrylic copolymer, tris-acrylic microspheres and polyethylene glycol (PEG) microspheres. Few studies are available on PEG embolics and their use for TACE. This review focuses on the efficacy and safety of TACE performed with PEG microspheres for the treatment of hepatocellular carcinoma and discusses future therapeutic advantages.

Hyperthermia combined with chemotherapy vs chemotherapy in patients with advanced pancreatic cancer: A multicenter retrospective observational comparative study.

BACKGROUND: Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electro-hyperthermia (mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer. AIM: To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer. METHODS: This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer (stage III and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128 (59%) of them were treated with CHT (no-mEHT) and 89 (41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT. RESULTS: Median patients' age was 67 years (range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group (20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses (45% vs 24%, P = 0.0018) and a lower number of progressions (4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions. CONCLUSION: mEHT seems safe and has beneficial effects on survival and tumor response of stage III-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results.

Immune response and locoregional treatments for peritoneal carcinomatosis.

Peritoneal Carcinomatosis (PC) is considered as a terminal disease with short survival. It is treated with palliative therapies, consisting of repeated drainages and sometimes instillation of chemotherapy. Since the nineties, surgery has been combined with more effective systemic chemotherapy, intraperitoneal chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PC. This combination therapy significantly increases the overall survival of selected PC patients. The understanding of how intraperitoneal chemotherapy and HIPEC can cure patients is still unclear. Experts hypothesized that the efficacy is obtained by the ability of high peritoneal drug exposure and hyperthermia to directly kill cancer cells. Several studies indicate that cancer cells death directly influences the response of the immune system. For this reason, the protective effect of intraperitoneal chemotherapy and HIPEC could be mediated by its ability to kill cancer cells in an immuno-genic way, causing an efficient anticancer immune response. In this review, we investigate the role of the innate peritoneal or locoregional therapy-induced immune response in PC therapy.

Transarterial chemoembolization alone or followed by bevacizumab for treatment of colorectal liver metastases.

AIMS: Bevacizumab (B) in association with systemic chemotherapy is commonly used for the treatment of colorectal cancer liver metastases. The aim of this study was to monitor tumor response, overall survival (OS) and progression-free survival (PFS) of patients with colorectal cancer liver metastases treated with transarterial chemoembolization (TACE) + B compared with TACE alone and to correlate the results with KRAS mutational status. PATIENTS & METHODS: This was an observational multicentric case-control study (NCT03732235) on the efficacy and safety of B administered after TACE. RESULTS: The disease control rate was significantly higher for the TACE + B than the TACE alone group (p < 0.001). KRAS wild-type patients had a significantly better disease control rate than those with KRAS mutations in the TACE + B group. Median OS and PFS were similar for the TACE + B and TACE groups, whereas median time to progression was significantly higher for the TACE + B group (p < 0.01). CONCLUSION: The combination of TACE with B may improve tumor response and delay disease progression.

Left ventricular hypertrophy in athletes: How to differentiate between hypertensive heart disease and athlete's heart.

Athlete's heart is typically accompanied by a remodelling of the cardiac chambers induced by exercise. However, although competitive athletes are commonly considered healthy, they can be affected by cardiac disorders characterised by an increase in left ventricular mass and wall thickness, such as hypertension. Unfortunately, training-induced increase in left ventricular mass, wall thickness, and atrial and ventricular dilatation observed in competitive athletes may mimic the pathological remodelling of pathological hypertrophy. As a consequence, distinguishing between athlete's heart and hypertension can sometimes be challenging. The present review aimed to focus on the differential diagnosis between hypertensive heart disease and athlete's heart, providing clinical information useful to distinguish between physiological and pathological remodelling.

The benefits of exercise in cancer patients and the criteria for exercise prescription in cardio-oncology.

Cancer and cardiovascular diseases are the leading causes of death in high-income countries. Cardiovascular complications can be found in cancer patients, being the result of so-called 'cardio-toxicity'. Therefore, it becomes essential to thoroughly investigate the origin of cardiac damage and the strategy to prevent it or to reverse the negative remodelling associated with cardiotoxicity. In this review the beneficial effects of physical exercise in cancer patients were analysed, particularly to prevent cardio-toxicity before its clinical manifestation. According to the relevance of exercise, we suggest strategies for exercise prescription with a tailored approach in these patients. In conclusion, physical exercise seems to be a promising and effective treatment for cancer patients during and after therapy and seems to counteract the negative effects induced by drugs on the cardiovascular system. Exercise prescription should be tailored according to patient's individual characteristics, to the drugs administered, to the personal history, and to his/her response to exercise, taking into account that different types of training can be prescribed according also to the patient's choice. A cardiological evaluation including exercise testing is essential for an appropriate prescription of exercise in these patients.

Modulated electro-hyperthermia in stage III and IV pancreatic cancer: Results of an observational study on 158 patients.

BACKGROUND: An increasing number of studies report the beneficial effects of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer; in particular, the use of modulated electro-hyperthermia (mEHT) results in increased survival and tumor response. AIM: To compare outcomes of CHT alone or in association with mEHT for the treatment of stage III and IV pancreatic cancer. METHODS: This was an observational retrospective study; data were collected for patients with stage III-IV pancreatic cancer that were treated with CHT alone or in combination with mEHT from 2003 to 2019. A total of 158 patients were included in the study out 270 patients screened in four Italian hospitals; 58 (37%) of these received CHT + mEHT and 100 (63%) CHT. CHT was mainly gemcitabine-based regimens in both groups. RESULTS: Overall (19.5 mo vs 11.02 mo, P < 0.001) and progression-free (12 mo vs 3 mo, P < 0.001) survival were better for the CHT + mEHT group compared to the CHT group. The association of mEHT resulted also in an improvement of tumor response with disease control rate 95% vs 58% (P < 0.001) at 3 mo. Toxicity was comparable in the two study groups, and mEHT related adverse events were limited in 8 patients presenting G1-2 skin burns. CONCLUSION: The addition of mEHT to systemic CHT improved overall and progression-free survival and local tumor control with comparable toxicity.

Updates of colorectal cancer liver metastases therapy: review on DEBIRI.

Colorectal cancer is a worldwide public health issue, presenting an advanced stage at diagnosis in more than 20% of patients. Liver metastases are the most common metastatic sites and are not indicated for resection in 80% of cases. Unresectable colorectal cancer liver metastases that are refractory to systemic chemotherapy may benefit from transarterial chembolization with irinotecan-loaded beads (DEBIRI). Several studies show the safety and efficacy of DEBIRI for the treatment of colorectal cancer liver metastases. The development of transarterial chembolization and the introduction of new embolics have contributed to better outcomes of DEBIRI. This article reviews the current literature on DEBIRI reporting its use, efficacy in terms of tumor response and survival and side effects.

A Narrative Review of Regional Hyperthermia: Updates From 2010 to 2019.

The role of hyperthermia (HT) in cancer therapy and palliative care has been discussed for years in the literature. There are plenty of articles that show good feasibility of HT and its efficacy in terms of tumor response and survival improvements. Nevertheless, HT has never gained enough interest among oncologists to become a standard therapy in clinical practice. The main advantage of HT is the enhancement of chemotherapy (CHT), radiotherapy (RT), chemoradiotherapy (CRT), and immunotherapy benefits. This effect has been confirmed in several types of tumors: esophageal, gastrointestinal, pancreas, breast, cervix, head and neck, and bladder cancers, and soft tissue sarcoma. HT effects include oxygenation and perfusion changes, DNA repair inhibition and immune system activation as a consequence of new antigen exposure. The literature shows a wide variety of randomized, nonrandomized, and observational studies and both prospective and retrospective data to confirm the advantage of HT association to CHT and RT. There are still many ongoing trials on this subject. This article summarizes the available literature on HT in order to update the current knowledge on HT use in association with RT and/or CHT from 2010 up to 2019.

Modulated Electro-Hyperthermia as Palliative Treatment for Pancreatic Cancer: A Retrospective Observational Study on 106 Patients.

Background: Pancreatic adenocarcinoma has a poor prognosis, resulting in a <10% survival rate at 5 years. Modulated electro-hyperthermia (mEHT) has been increasingly used for pancreatic cancer palliative care and therapy. Objective: To monitor the efficacy and safety of mEHT for the treatment of advanced pancreatic cancer. Methods: We collected data retrospectively on 106 patients affected by stage III-IV pancreatic adenocarcinoma. They were divided into 2 groups: patients who did not receive mEHT (no-mEHT) and patients who were treated with mEHT. We performed mEHT applying a power of 60 to 150 W for 40 to 90 minutes. The mEHT treatment was associated with chemotherapy and/or radiotherapy for 33 (84.6%) patients, whereas 6 (15.4%) patients received mEHT alone. The patients of the no-mEHT group received chemotherapy and/or radiotherapy in 55.2% of cases. Results: Median age of the sample was 65.3 years (range = 31-80 years). After 3 months of therapy, the mEHT group had partial response in 22/34 patients (64.7%), stable disease in 10/34 patients (29.4%), and progressive disease in 2/34 patients (8.3%). The no-mEHT group had partial response in 3/36 patients (8.3%), stable disease in 10/36 patients (27.8%), and progressive disease in 23/36 patients (34.3%). The median overall survival of the mEHT group was 18.0 months (range = 1.5-68.0 months) and 10.9 months (range = 0.4-55.4 months) for the non-mEHT group. Conclusions: mEHT may improve tumor response and survival of pancreatic cancer patients.

Cardiac Magnetic Resonance Normal Reference Values of Biventricular Size and Function in Male Athlete's Heart.

OBJECTIVES: The aim of this meta-analysis was to derive normal reference values of biventricular size and function estimated by cardiac magnetic resonance (CMR) in competitive athletes. BACKGROUND: Exercise-induced enlargement of cardiac chambers is commonly observed in competitive athletes. However, ventricular dilatation is also a common phenotypic expression of life-threatening cardiomyopathies. The use of CMR for the exclusion of pathology is growing. However, normal reference values have not been established for athletes. METHODS: The authors conducted a systematic review of English-language studies in the MEDLINE, Scopus, and Cochrane databases investigating biventricular size and function by CMR in athletes. Athletes were divided into endurance, combined, and mixed groups according to the sport practiced. The potential impact of training volume was also evaluated. RESULTS: Twenty-seven studies and 983 competitive athletes were included for CMR quantification of biventricular size and function. In this review, normal reference values are presented for biventricular size and function to be applied to male competitive athletes according to the disciplines practiced. A significant impact of training volume was demonstrated for the right ventricle: athletes practicing the largest number of training hours per week were those exhibiting the greatest degree of right ventricular remodeling. Notably, biventricular function was not significantly affected by training volume. CONCLUSIONS: The present meta-analysis defines the normal limits of biventricular size and function estimated by CMR in competitive athletes. The authors suggest using these normal reference values as an alternative to standard upper limits derived from the general population when interpreting CMR images in athletes.

Modulated Electrohyperthermia in Integrative Cancer Treatment for Relapsed Malignant Glioblastoma and Astrocytoma: Retrospective Multicenter Controlled Study.

BACKGROUND: There are interesting studies on glioma therapy with modulated electrohyperthermia (mEHT), which combines heat therapy with an electric field. Clinical researchers not only found the mEHT method feasible for palliation but also reported evidence of therapeutic response. PURPOSE: To study the efficacy and safety of mEHT for the treatment of relapsed malignant glioma and astrocytoma versus best supportive care (BSC). METHODS: We collected data retrospectively on 149 patients affected by malignant glioma and astrocytoma. Inclusion criteria were informed consent signed; >18 years old; histological diagnosis of malignant glioma or astrocytoma; relapsed after surgery, adjuvant temozolomide-based chemotherapy, and radiotherapy; and indication for treatment with mEHT in palliative setting. mEHT was performed with capacitive coupling technique keeping the skin surface at 26°C and the tumor temperature at 40°C to 42.5°C for > 90% of treatment duration (20-60 minutes). The applied power was 40 to 150 W using a step-up heating protocol. Results from patients treated with mEHT were compared with those treated with BSC. RESULTS: A total of 149 consecutive patients were enrolled in the study, 111 (74%) had glioblastoma multiforme (GBM), and 38 (26%) had astrocytoma (AST). mEHT was performed for 28 (25%) of GBM and 24 (63%) of AST patients. Tumor response at the 3-month follow-up was observed in 29% and 48% of GBM and AST patients after mEHT, and in 4% and 10% of GBM and AST patients after BSC, respectively. The survival rate at first and second year in the mEHT group was 77.3% and 40.9% for AST, and 61% and 29% for GBM, respectively. The 5-year overall survival of AST was 83% after mEHT versus 25% after BSC and 3.5% after mEHT versus 1.2% after BSC for GBM. The median overall survival of mEHT was 14 months (range 2-108 months) for GBM and 16.5 months (range 3-156 months) for the AST group. We observed 4 long-term survivors in the AST and 2 in the GBM group. Two of the long survivors in AST and 1 in GBM group were treated by mEHT. CONCLUSIONS: mEHT in integrative therapy may have a promising role in the treatment and palliation of relapsed GBM and AST.

Hypoxic pelvic perfusion with cisplatin and mitomycin C in multidisciplinary palliative treatment of patients with unresectable recurrent rectal cancer: a retrospective study.

BACKGROUND: Patients with unresectable recurrent rectal cancer that progresses after systemic chemotherapy and radiotherapy may be candidates for palliation with hypoxic pelvic perfusion (HPP). The aim of this observational retrospective study was to evaluate if a multimodality treatment including HPP and targeted-therapy may be useful to prolong clinical responses and survival of these patients. METHODS: Thirty-seven patients with unresectable recurrent rectal cancer in progression after standard treatments underwent repeated HPP with mitomycin C (25 mg/m2) and cisplatin (70 mg/m2). Twenty patients, exhibiting epidermal growth factor receptor (EGFR) overexpression, also received cetuximab targeted-therapy, following the ultimate HPP treatment. RESULTS: Following initial HPP treatment, median progression-free survival was 7 months (range: 5-19 months), median time-to-death or termination of follow-up was 13 months (range: 9-18 months), one-year survival-rate was 59.45%, two-year survival rate was 10.81%, and three-year survival rate was 2.7%. Survival was significantly influenced by cetuximab targeted-therapy post-HPP and the presence of additional metastatic sites (P<0.03). CONCLUSIONS: Repeated HPP treatments with mitomycin C plus cisplatin, followed by cetuximab targeted-therapy, may represent a safe and efficacious palliative therapy in patients with unresectable recurrent rectal cancer, in progression following standard systemic chemo- and radio-therapy, and thus warrants confirmation in a larger phase III study.

Palliation with a multimodality treatment including hypoxic pelvic perfusion for unresectable recurrent rectal cancer: outcomes based on a retrospective study.

Patients with unresectable recurrent rectal cancer that progresses after systemic chemotherapy and radiotherapy are candidates for palliation with hypoxic pelvic perfusion (HPP). The aim of this observational retrospective study was to evaluate if a multimodality treatment including HPP and targeted-therapy may be useful to prolong clinical responses and survival of these patients. From a cohort of 77 patients with unresectable recurrent rectal cancer in progression after standard treatments and submitted to HPP, 21 patients underwent repeat HPP using mitomycin C (MMC) at the dose of 25 mg/m2. After the last HPP, 7 patients received a targeted-therapy with cetuximab according to overexpression of epidermal growth factor receptor in recurrence cancer cells. The median overall survival of these 21 patients from the diagnosis of unresectable recurrent rectal cancer was 23 months (iqr 18-24). After the first HPP, the median survival of the 21 patients until death or end of follow-up was 10 months (iqr 9-13). The 1-year and 2-year survival rates were 71.4%, and 4.8%, respectively. From the first HPP, age > 60 years, a recurrence shrinkage of at least 30% (partial response), and the addition of a post-HPP targeted-therapy with cetuximab significantly affected survival (P < 0.04). In conclusion, repeated MMC-HPP followed by targeted-therapy seems to be an effective palliative treatment for patients with unresectable recurrent rectal cancer in progression after systemic chemotherapy and radiation but the results of this study have to be confirmed by a larger phase III trial.