Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design.

BACKGROUND: Current standard of care for metastatic castration-sensitive prostate cancer supplements androgen deprivation therapy with either docetaxel, second-generation hormonal therapy, or radiotherapy. We aimed to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy, in addition to standard of care. METHODS: We conducted an open-label, randomised, phase 3 study with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Belgium, France, Ireland, Italy, Romania, Spain, and Switzerland. Eligible patients were male, aged 18 years or older, with histologically confirmed or cytologically confirmed de novo metastatic prostate adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0-1 (or 2 due to bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m2 once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone. Neither the investigators nor the patients were masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival. Abiraterone efficacy was first assessed in the overall population and then in the population who received androgen deprivation therapy with docetaxel as standard of care (population of interest). This study is ongoing and is registered with ClinicalTrials.gov, NCT01957436. FINDINGS: Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled (one patient subsequently withdrew consent for analysis of his data) and assigned to receive standard of care (n=296), standard of care plus radiotherapy (n=293), standard of care plus abiraterone (n=292), or standard of care plus radiotherapy plus abiraterone (n=291). Median follow-up was 3·5 years (IQR 2·8-4·6) for radiographic progression-free survival and 4·4 years (3·5-5·4) for overall survival. Adjusted Cox regression modelling revealed no interaction between abiraterone and radiotherapy, enabling the pooled analysis of abiraterone efficacy. In the overall population, patients assigned to receive abiraterone (n=583) had longer radiographic progression-free survival (hazard ratio [HR] 0·54, 99·9% CI 0·41-0·71; p<0·0001) and overall survival (0·82, 95·1% CI 0·69-0·98; p=0·030) than patients who did not receive abiraterone (n=589). In the androgen deprivation therapy with docetaxel population (n=355 in both with abiraterone and without abiraterone groups), the HRs were consistent (radiographic progression-free survival 0·50, 99·9% CI 0·34-0·71; p<0·0001; overall survival 0·75, 95·1% CI 0·59-0·95; p=0·017). In the androgen deprivation therapy with docetaxel population, grade 3 or worse adverse events occurred in 217 (63%) of 347 patients who received abiraterone and 181 (52%) of 350 who did not; hypertension had the largest difference in occurrence (76 [22%] patients and 45 [13%], respectively). Addition of abiraterone to androgen deprivation therapy plus docetaxel did not increase the rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared with androgen deprivation therapy plus docetaxel alone. INTERPRETATION: Combining androgen deprivation therapy, docetaxel, and abiraterone in de novo metastatic castration-sensitive prostate cancer improved overall survival and radiographic progression-free survival with a modest increase in toxicity, mostly hypertension. This triplet therapy could become a standard of care for these patients. FUNDING: Janssen-Cilag, Ipsen, Sanofi, and the French Government.

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

BACKGROUND: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING: Nanobiotix SA.

Mind the Gap Between Scientific Literature Recommendations and Effective Implementation. Is There Still a Role for Surgery in the Treatment of Locally Advanced Cervical Carcinoma?

According to evidence accumulated in the last years, many cancer centers recommend a treatment plan based solely on chemo-radiotherapy and exclude surgery from the treatment options in locally advanced cervical cancer (LACC). In Romania, surgery was at the forefront of therapeutic options. Nevertheless, current data shows that in fact, a large number of patients are still referred to surgery in various stages of diagnosis and treatment. It was noted that recommendations may differ, in spite of the wide dissemination of the literature data.Works published so far, discussing the role of surgery in LACC treatment shows a lack of consensus. A group of experts in oncology (SURCECAN research group - Surgery of Cervical Cancer) met for a session of the Romanian Surgical Society (Bucharest) on April 18, 2018. They found that LACC therapeutic strategy in Romania may differ somewhat from the European recommendations.On top of that, late enrolement to RT and low acces to specialized centers are the problem. Performing surgery not only allows the evaluation of the pathological response to chemo-radiotherapy, but also achieves a better local control. In conclusion, there is still a place for surgery within locally advanced cervical cancer treatment options. More trials need to be carried out in order to confirm the findings and establish high levels of confidence for each piece of information provided.

SChitosan-capped gold nanoparticles impair radioresistant glioblastoma stem-like cells.

PURPOSE: Glioblastoma is a rapidly evolving lethal disease mainly due to its highly chemo- and radioresistant glioblastoma stem cells (GSCs). Herein, we tested if chitosan-capped gold nanoparticles (Chit-GNPs) may overcome the limitations of drug concentrations by increased cell internalization in GSCs and if such GNPs could enhance the response to irradiation. METHODS: Chitosan was used for Chit-GNP synthesis as a reducing and stabilizing agent. Chit-GNPs were characterized by spectroscopy, dark field, transmission electron microscopy and zeta potential measurements. Patient-derived GSCs and human osteoblasts were treated with increasing concentrations of nanoparticles and irradiated. The uptake and cytotoxicity of Chit-GNPs were compared to that of uncoated GNPs. RESULTS: The positively-charged, 26 nm-sized, spherical Chit-GNPs, showed a huge intracellular accumulation into the cytosol, lysosomes and near the nucleus, whereas no uncoated GNPs were internalized within GSCs. Surprisingly, Chit-GNPs were highly cytotoxic for GSCs irrespective of cell irradiation, that failed to add an additional benefit when combined with Chit-GNPs/GNPs. Moreover, Chit-GNPs were selectively cytotoxic for GSCs and did not affect the normal cells, despite an increased nanoparticle internalization. CONCLUSIONS: The important Chit-GNP internalization and their selective cytotoxicity for GSCs make this compound a potential novel anticancer agent and a promising backbone for drug delivery in glioblastoma.

Nanoparticles for Targeting Intratumoral Hypoxia: Exploiting a Potential Weakness of Glioblastoma.

Extensive hypoxic regions are the daunting hallmark of glioblastoma, as they host aggressive stem-like cells, hinder drug delivery and shield cancer cells from the effects of radiotherapy. Nanotechnology could address most of these issues, as it employs nanoparticles (NPs) carrying drugs that selectively accumulate and achieve controlled drug release in tumor tissues. Methods overcoming the stiff interstitium and scarce vascularity within hypoxic zones include the incorporation of collagenases to degrade the collagen-rich tumor extracellular matrix, the use of multistage systems that progressively reduce NP size or of NP-loaded cells that display inherent hypoxia-targeting abilities. The unfavorable hypoxia-induced low pH could be converted into a therapeutical advantage by pH-responsive NPs or multilayer NPs, while overexpressed markers of hypoxic cells could be specifically targeted for an enhanced preferential drug delivery. Finally, promising new gene therapeutics could also be incorporated into nanovehicles, which could lead to silencing of hypoxia-specific genes that are overexpressed in cancer cells. In this review, we highlight NPs which have shown promising results in targeting cancer hypoxia and we discuss their applicability in glioblastoma, as well as possible limitations. Novel research directions in this field are also considered.

Repositioning metformin in cancer: genetics, drug targets, and new ways of delivery.

After sitting many years on the shelves of drug stores as a harmless antidiabetic drug, metformin comes back in the spotlight of the scientific community as a surprisingly effective antineoplastic drug. Metformin targets multiple pathways that play pivotal roles in cancer progression, impacting various cellular processes, such as proliferation, cell death, metabolism, and even the cancer stemness features. The biomolecular characteristics of tumors, such as appropriate expression of organic cation transporters or genetic alterations including p53, K-ras, LKB1, and PI3K may impact metformin's anticancer efficiency. This could indicate a need for tumor genetic profiling in order to identify patients most likely to benefit from metformin treatment. Considering that the majority of experimental models suggest that higher, supra-clinical doses of metformin should be used in order to obtain an antineoplastic effect, new ways of drug delivery could be developed, such as metformin-loaded nanoparticles or incorporation of metformin into microparticles used in transarterial chemoembolization, with the aim of obtaining higher intratumoral drug concentrations and a targeted therapy which will ultimately maximize metformin's efficacy.

Relationship of endothelial cell selective adhesion molecule to markers of oxidative stress in type 2 diabetes.

BACKGROUND: Endothelial dysfunction is an important contributor to micro and macrovascular complications of type 2 diabetes (T2D) and is reflected by increased systemic oxidative stress. Endothelial cell selective adhesion molecule (ESAM) influences endothelial function. We aimed to assess, for the first time to our knowledge, the relationship of soluble ESAM to markers of systemic oxidative stress. MATERIALS AND METHODS: ESAM, malondialdehyde (MDA) level and catalase activity were determined in 54 T2D patients and 43 controls. RESULTS: T2D patients had significantly higher ESAM when compared to controls (16.07 ± 5.77 µg/L versus 8.57 ± 5.28 µg/L, p < 0.0001), they also had higher MDA level (3.88 ± 1.50 µmol/L vs. 1.58 ± 0.72 µmol/L, p < 0.0001) and lower catalase activity (3.07 (2.63-3.44) U/mg vs. 8.72 (4.55-10.46) U/mg, p < 0.0001). In T2D patients ESAM was inversely related to catalase activity (r = -0.27, p = 0.04), relationship to MDA level was direct but not significant (r = 0.16, p = 0.24). MDA concentration correlated inversely to catalase activity (r = -0.28, p = 0.04). In multiple regression catalase activity remained significantly correlated to ESAM (p = 0.02) and MDA level was significantly related to glycated hemoglobin (p = 0.01); there was trend towards a positive correlation of MDA level to ESAM (p = 0.08). When patients were divided according to oxidative stress, those with increased oxidative stress (defined as MDA concentration > 2.98 µmol/L and catalase activity < 3.38 U/mg) had higher ESAM than the rest of the patients (17.99 ± 5.02 µg/L vs. 14.29 ± 5.94 µg/L p = 0.01). CONCLUSION: ESAM is higher in T2D than in controls and parallels oxidative stress: ESAM is inversely related to catalase activity and higher ESAM is found in T2D patients with increased oxidative stress.

Management of bone metastases in patients with castration-resistant prostate cancer.

Bone metastases are a very common problem in prostate cancer. They are associated with considerable morbidity, adversely affect quality of life and frequently lead to advanced bone events (so-called skeletal-related events, SREs); SREs include fractures, spinal cord compression and the requirement for bone surgery or bone radiation. The aim of this paper was to evaluate currently available treatment options in the prevention and management of SREs and bone metastases in men with castration-resistant prostate cancer and to outline the importance of interdisciplinary management strategies. It also discusses the diagnostic workup of osseous metastases and practical considerations for the utilization of bone-targeted therapies in accordance with current guidelines to provide a consensus for special and/or difficult clinical situations.

The androgen receptor remains a key player in metastatic hormone-refractory prostate cancer. Implications for new treatments.

Metastatic castration-resistant prostate cancer (mCRPC) shows a number of adaptive mechanisms that facilitate continued androgen receptor (AR) dependent tumor growth. In this article we reviewed the subsequent hormonal manipulation in mCRPC, including the recently approved new drugs, in relation to the AR dependent and independent growth mechanisms. Maintaining castrate levels of testosterone is mandatory. The AR amplification, a process that can occur within the hypersensitive AR escape route, can be fought by using high dose antiandrogen (bicalutamide 150mg), change in antiandrogen preparation or the use of enzalutamide. Switch to another antiandrogen, the use of LHRH antagonists, change to another LHRH agonist, bilateral orchidectomy, adrenals' inhibition and the blockade of intratumor testosterone synthesis are several ways to counter the increased AR sensitivity. Increased androgen levels can be reduced by the use of ketoconazole, dexamethasone, abiraterone acetate or 5α-reductase inhibitors. Antiandrogen withdrawal and enzalutamide can be used to counter the promiscuous AR escape route. The use of metformin, cetuximab or cabozantinib could represent ways to overcome the outlaw pathway, but further studies are needed to show the efficacy of these drugs in mCRPC. Bcl-2 inhibitors, emerging drugs still in experimental phase, show great potential in counteracting the bypass pathway. Docetaxel and cabazitaxel, the standard chemotherapy of mCRPC, are the treatment of choice when androgen-independent prostate cancer cells are selected (as supported by the lurker cell pathway).The correct and rational use of all these drugs may delay by months or even years the need to administer chemotherapy in patients with mCRPC but some AR targeted therapies may impair the subsequent response to chemotherapy.

Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells.

PURPOSE: Glioblastoma stem cells (GSCs), responsible for the dismal disease prognosis after conventional treatments, are driven by overactive signaling pathways, such as PI3K/ AKT/mTOR and RAS/RAF/MAPK. The objective of our study was to target in vitro-GSCs by combining metformin (Met) as a mTOR inhibitor, with sorafenib (Soraf) as a RAF inhibitor. METHODS: GSCs cultured under basal conditions were treated with Met, temozolomide (TMZ), Soraf, Met+TMZ and Met+Soraf; as untreated arm served as control. At 4 hrs of drug exposure, we measured the level of reactive oxygen species (ROS) by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, apoptosis by prodium iodide (PI)-V Annexin staining and efflux pump activity by using the fluorescent dye rhodamine 123. At 24 hrs, we measured cell proliferation by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis and malondialdehyde (MDA) levels. MTT results were compared with corresponding measurements on cultures of non-stem glioblastoma cells and osteoblasts. RESULTS: Met+Soraf exerted the highest antiproliferative effects in GSCs and non-stem glioblastoma cells (p<0.001). Both Met and Soraf monotherapy exhibited a selective cytotoxic effect on GSCs (p<0.001), while no effect was detected on non-stem glioblastoma cells (p>0.05). Soraf, but not Met, impacted the proliferation of normal cells. Soraf displayed synergism with Met in producing high levels of ROS, decreasing efflux pump activity and generating the highest apoptotic rates when compared to either drug alone (p<0.001). CONCLUSION: GSCs were highly sensitive to the combination of Met and Soraf which reduced cell proliferation, increased oxidative stress, inhibited efflux pump activity and ultimately killed GSCs. We strongly believe that these results warrant further in vivo exploration.

Endothelial cell-selective adhesion molecule in diabetic nephropathy.

BACKGROUND: Endothelial cell-selective adhesion molecule (ESAM) contributes to the integrity of tight junctions and modulates endothelial function. ESAM has been linked to experimental diabetic nephropathy; its soluble fraction is related to atherosclerosis in humans. In this cross-sectional observational study, we describe for the first time serum ESAM in type 2 diabetic patients with different stages of chronic kidney disease (CKD) and its relationship to vascular endothelial growth factor-A (VEGF-A). Materials and methods We included diabetic patients with different stages of CKD and controls. History, laboratory evaluation, serum ESAM and VEGF-A and urinary albumin/creatinine ratio were obtained. RESULTS: Endothelial cell-selective adhesion molecule was higher in non-CKD diabetic patients 13.80 (6.15-18.70) ng/mL (n=45) than controls 7.30 (4.60-9.40) ng/mL (n=48), P=0.001. VEGF-A had a similar pattern: 71.3 (54.75-120.70) vs. 43.20 (30.1-65.90) pg/mL, P<0.0001. ESAM was 10.4 (5.6-17.4) ng/mL in predialysis CKD patients (n=59) and 22.35 (8.55-29.95) ng/mL in dialysis patients (n=36), P<0.001. Patients with glomerular filtration rate (GFR)<15 mL/min had the highest ESAM (P=0.003). ESAM was similar in normoalbuminuric, microalbuminuric and proteinuric patients. ESAM was directly correlated with the duration of diabetes (r(2)=0.048, P=0.009), C-reactive protein (r(2)=0.028, P=0.05), VEGF-A (r(2)=0.040, P=0.01) and inversely with HbA1C (r(2)=0.036, P=0.03), haemoglobin (r(2)=0.062, P=0.005) and albumin (r(2)=0.0·40, P=0.026). In multiple regression diabetes duration, HbA1C and VEGF-A were significant predictors of ESAM. In controls, ESAM was inversely related to VEGF (r(2)=037, P=0.01). CONCLUSION: Endothelial cell-selective adhesion molecule and VEGF-A are higher in patients with diabetes than in controls. The highest ESAM is found in dialysis patients. ESAM correlates with diabetes duration and control, inflammation and VEGF-A in patients with diabetes, but not in controls.

Plasma adiponectin is related to the progression of kidney disease in type 2 diabetes patients.

BACKGROUND: Adiponectin, an anti-inflammatory and insulin-sensitizing cytokine, has been shown to reduce proteinuria and glomerulosclerosis in experimental models. We assessed the relationship of plasma adiponectin to the progression of kidney disease in type 2 diabetes (T2D) patients. METHODS: T2D nonnephrotic patients with glomerular filtration rate (GFR) >30 ml/min and without acute cardiovascular/inflammatory conditions were included. Laboratory standard evaluation, urinary albumin/creatinine ratio (UACR), total plasma adiponectin, and CRP (C-reactive protein) were determined at inclusion and the end of study. RESULTS: Eighty-six patients (62.79% male) were followed up for 20.53±5.46 months. Baseline GFR was 72.85±26.29 ml/min and UACR was 20.53 (interquartile range 6.82-86.39) mg/g. At baseline adiponectin was significantly correlated to UACR (r =0.40, p =0.0001), HDL cholesterol (r =0.30, p =0.005), GFR (r =- 0.23, P =0.04), body mass index (BMI) (r =- 0.26, P =0.02) and waist circumference (r =-0.27, p =0.01). In multiple regression UACR (p =0.0003) and BMI (p =0.03) were significantly related to baseline adiponectin. The progression of kidney disease was estimated as the difference (D) between end and baseline UACR/month and between end and baseline GFR/month. None of the baseline parameters correlated to ΔGFR, but adiponectin inversely (r =- 0.26, p =0.02) correlated to ΔUACR. In multiple regression only adiponectin (p <0.0001) predicted ΔUACR. A computed progression index (PI) resulting from a linear combination of GFR and UACR was also used to assess progression. Baseline adiponectin was significantly correlated to ΔPI between end of study and baseline (r =- 0.43, p <0.0001), and predicted ΔPI in multiple regression (p =0.009). CONCLUSION: Low plasma adiponectin predicts progression of kidney disease in T2D patients.

Real-World Patterns and Decision Drivers of Radiotherapy for Lung Cancer Patients in Romania: RADIO-NET Study Results.

Radiotherapy (RT) plays a crucial role in all stages of lung cancer. Data on recent real-world RT patterns and main drivers of RT decisions in lung cancer in Romania is scarce; we aimed to address these knowledge gaps through this physician-led medical chart review in 16 RT centers across the country. Consecutive patients with lung cancer receiving RT as part of their disease management between May-October 2019 (pre-COVID-19 pandemic) were included. Descriptive statistics were generated for all variables. This cohort included 422 patients: median age 63 years, males 76%, stages I-II 6%, III 43%, IV 50%, mostly adeno- and squamous cell carcinoma (76%), ECOG 0-1 50% at the time of RT. Curative intent RT was used in 36% of cases, palliative RT in 64%. Delays were reported in 13% of patients, mostly due to machine breakdown (67%). Most acute reported RT toxicity was esophagitis (19%). Multiple disease-, patient-, physician- and context-related drivers counted in the decision-making process. This is the first detailed analysis of RT use in lung cancer in Romania. Palliative RT still dominates the landscape. Earlier diagnosis, coordinated multidisciplinary strategies, and the true impact of the multimodal treatments on survival are strongly needed to improve lung cancer outcomes.

Final Safety and Health-Related Quality of LIfe Results of the Phase 2/3 Act.In.Sarc Study With Preoperative NBTXR3 Plus Radiation Therapy Versus Radiation Therapy in Locally Advanced Soft-Tissue Sarcoma.

PURPOSE: Act.In.Sarc (NCT02379845) demonstrated that the first-in-class radioenhancer NBTXR3, activated by preoperative radiation therapy (RT), doubled the rate of pathologic complete response after resection compared with preoperative RT alone in adult patients with locally advanced soft tissue sarcoma of the extremity or trunk wall (16.1% vs 7.9%, P = .045), and more patients achieved R0 resections (77.0% vs 64.0%, P = .042). These are the toxicity and health-related quality of life (HRQoL) results. METHODS AND MATERIALS: Act.In.Sarc randomized eligible patients 1:1 to either NBTXR3 (single intratumoral injection, volume equivalent to 10% of baseline tumor volume, at 53.3 g/L) activated by external-beam RT (arm A) or external-beam RT alone (arm B) (50 Gy in 25 fractions), followed by surgery in both arms. Here, we report the safety analyses in the all-treated population with a long-term follow-up of at least 2 years, and HRQoL in the intention-to-treat full analysis set. RESULTS: During the on-treatment period, serious adverse events (SAEs) of all grades related to NBTXR3 occurred in 10.1% (9/89) of patients (arm A), and SAEs related to RT occurred in 5.6% (5/89) (arm A) versus 5.6% (5/90) (arm B); postsurgery hospitalization owing to SAEs occurred in 15.7% (14/89) (arm A) versus 24.4% (22/90) (arm B). During the follow-up period, posttreatment SAEs (regardless of relationship) occurred in 13.5% (12/89) (arm A) versus 24.4% (22/90) (arm B). NBTXR3 did not negatively affect HRQoL; during the follow-up period, there was an improvement in most mean Toronto extremity salvage, EuroQoL 5-dimension (EQ-5D), EQ5D02-EQ visual analog scale, reintegration to normal living index, and musculoskeletal tumor rating scale scores. CONCLUSIONS: NBTXR3 did not negatively affect safety or HRQoL. Long-term safety results reinforce the favorable benefit-risk ratio of NBTXR3 plus RT.

Difficulties in diagnosing anorectal melanoma: A case report and review of the literature.

BACKGROUND: Anorectal melanoma is a tumour that is difficult to identify due to its rarity and variability of presentation. Insufficient data published in the literature do not allow for diagnostic and treatment guidelines to be established. Anorectal melanoma has the worst prognosis among mucosal melanomas and is frequently misdiagnosed by standard identification methods. CASE SUMMARY: A 66-year-old woman presented with intermittent anal bleeding, pain, and tenesmus in the past month, with no associated weight loss. Colonoscopy revealed a cauliflower-like tumour with a diameter of 1.5 cm, with exulcerated areas and an adherent clot but without obstruction. Biopsy results identified an inflammatory rectal polyp with nonspecific chronic rectitis. Tumour markers CA 19-9 and CEA were within the normal range. After 6 mo, due to the persistence of symptoms, a pelvic magnetic resonance imaging scan was performed. A lesion measuring 2.8 cm × 2.7 cm × 2.1 cm was identified at the anorectal junction, along with two adjacent lymphadenopathies. No distant metastases were detected. Immunohistochemistry was performed on the second set of biopsies, and a diagnosis of anorectal melanoma was established. Surgical treatment by abdominoperineal resection was performed. Evolution was marked by the appearance of lung metastases at 1 mo postoperatively, detected on a positron emission tomography-computer tomography scan, and perineal recurrence after 5 mo. After molecular testing, the patient was included in an immunotherapy trial. CONCLUSION: This case highlights the difficulty of establishing a definitive early diagnosis of anorectal melanoma, the importance of performing histological analysis on a well-represented biopsy specimen, and the poor prognosis, even with radical surgery.

Microwave ablation in the treatment of liver tumors. A better tool or simply more power?

It has been a long time since tumor ablation was first tested in patients with liver cancer, especially hepatocellular carcinoma. Since than it has become a first line treatment modality for hepatocellular carcinoma. Over the years, the indications of thermal ablation have expanded to colorectal cancer liver metastases and intrahepatic cholangiocarcinoma as well. Together with the new indication for ablation, new ablation devices have been developed as well. Among them microwave ablation shows potential in replacing radiofrequency ablation as the preferred method of thermal ablation in liver cancer. The debate whether radiofrequency or microwave ablation should be the preferred method of treatment in patients with liver cancer remains open. The main purpose of this review is to offer some answers to the question: Microwave ablation in liver tumors: a better tool or simply more power? Various clinical scenarios will be analyzed including small, medium, and intermediate size hepatocellular carcinoma, colorectal cancer liver metastases and intrahepatic cholangiocarcinoma. Furthermore, the advantages, limitations, and technical considerations of MWA treatment will be provided also.

Local staging of prostate cancer with multiparametric-MRI: accuracy and inter-reader agreement.

BACKGROUND: The accuracy of prostate cancer local staging at the time of diagnosis directly influences patient prognosis and treatment. AIM: To evaluate the diagnostic performance and interobserver variability of mp-MRI in local staging of prostate cancer, using the histopathologic findings at prostatectomy as the reference standard. METHODS: Fifty patients (mean age 64.4±7.2) with biopsy confirmed prostate cancer were included in this prospective study. All patients were examined with mp-MRI before radical prostatectomy and images were read by three independent radiologists. Sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and accuracy rate were calculated and compared for all three readers. Interobserver agreement was evaluated using Kappa Cohen coefficient of agreement. RESULTS: The overall Se, Sp, PPV, NPV and accuracy rates for detecting extraprostatic tumor extension (EPE) ranged between 76.5-94.1%, 45.5-84.9%, 43.8-76.2%, 83.3-96.6% and 58-88%. For evaluation of seminal vesicle invasion (SVI), the overall Se, Sp, PPV, NPV and accuracy rates ranged between 57.1-85.7%, 86.1-97.7%, 40.0-85.7%, 92.5-97.7% and 82-96%, respectively. The overall Kappa Cohen coefficient of agreement varied between 0.349-0.638 for EPE and between 0.507-0.668 for SVI. CONCLUSIONS: Our results showed that 1.5T mp-MRI is a reliable method for local staging of prostate cancer, with good diagnostic performance in detecting EPE and SVI. The overall interobserver agreement rates between readers with the same level of experience in prostate MRI ranged from fair to good in the evaluation of EPE and from moderate to good for the assessment of SVI.

The in vivo modulatory effects of Cornus mas extract on photodynamic therapy in experimental tumors.

BACKGROUND: Photodynamic therapy (PDT) is a treatment of cancer due to its ability to induce cell death, oxidative stress and acute inflammatory reaction in targeted sites. To optimize the effect of PDT the addition of some compounds with supplementary cytotoxic effect on tumor cells was tried. METHODS: The study was performed on 35 Wistar male albino rats with Walker 256 carcinosarcoma. The animals were randomly assigned in seven groups (n = 5) and treated as follows: group 1 - control; group 2 - Cornus mas (CM) extract 15 mg/kg b.w., administered for 7 days; group 3 - CM extract administered for 7 days followed by irradiation (CM + IR); group 4 - one dose of tetra-p-sulfonato-phenyl-porphyrin (TSPP) 10 mg/kg b.w.; group 5 - TSPP + IR; group 6 - CM extract administered daily for 7 days before TSPP and IR (CM + TSPP + IR); group 7 - TSPP + IR followed by CM administered for 7 days (TSPP + IR + CM). RESULTS: The results showed that MDA and GSSG levels increased after PDT in parallel with the increasing of COX-2 expression and DNA damage. Apoptotic and necrotic index enhanced in TSPP + IR, effect improved by CM association before PDT. CM + TSPP + IR regimen also induced more intense inflammatory reactions, increased COX-2 expression, determined DNA damage, apoptosis and necrosis, compared to the TSPP + IR + CM group. Both combined therapeutic regimens reduced MDA levels in tumor tissue, especially CM + TSPP + IR and increased the antioxidant defense and iNOS expression. CONCLUSIONS: Our results demonstrated that CM associated before PDT had beneficial effects in PDT and may represent a promising option in PDT strategies.

What is the real impact of bone pain on survival in patients with metastatic hormone-refractory prostate cancer treated with docetaxel?

OBJECTIVES: To determine the benefit of starting early chemotherapy with docetaxel (the recommended first-line treatment) for patients with asymptomatic metastatic hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Data were analysed from 145 patients with HRPC treated with chemotherapy between February 2000 and June 2002 in one French centre. Eligible patients were categorized into three groups according to the bone pain at baseline, i.e. minimal/no pain, mild, and moderate/severe pain. The primary endpoint was the effect of bone pain on overall survival (OS). RESULTS: Docetaxel was administered to 67% of patients. The risk of death was 1.56 and 2.11 times higher for patients with mild or moderate/severe pain than for those with minimal/no pain (P = 0.027). The median (95% confidence interval (CI)) OS was 23.1 (18.5-27.6) and 14.1 (8.9-19.2) months (P = 0.001, log-rank-test) for patients with minimal pain or no pain treated with docetaxel-based chemotherapy compared with mitoxantrone, respectively. The prostate-specific antigen doubling time (PSA-DT) had a significant effect on OS in patients with minimal/no pain, with a median of 32.4 and 16.5 months for a PSA-DT of >or=45 and <45 days, respectively (P < 0.001). CONCLUSIONS: Our results suggest that patients with HRPC and minimal or no bone pain could have better survival than those with mild pain or moderate to severe pain, independent of the treatment administered. In addition, patients with HRPC and minimal or no bone pain treated with docetaxel-based chemotherapy have a significantly better OS than those treated with mitoxantrone. The PSA-DT can be useful to identify asymptomatic patients who are candidates for early treatment.