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.

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.

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.

Real-Time Contrast-Enhanced-Guided Biopsy Compared with Conventional Ultrasound-Guided Biopsy in the Diagnosis of Hepatic Tumors on a Background of Advanced Chronic Liver Disease: A Prospective, Randomized, Clinical Trial.

We aimed to compare contrast-enhanced-guided liver biopsy (CEUSLB) and ultrasound-guided liver biopsy (USLB) in the diagnosis of focal liver lesions (FLLs) developed on a background of advanced chronic liver disease (ACLD). Between 2011 and 2019, patients diagnosed with liver tumors on a background of ACLD were evaluated for inclusion in the study. Patients were randomly assigned to the CEUSLB or USLB group. In total, 144 patients were randomly assigned to either CEUSLB (n = 79) or USLB (n = 65). Overall, in the CEUSLB group, the sensitivity was significantly better (94.74% vs. 74.6%, respectively; p = 0.001). Both the fragment length of the biopsy specimen and the single puncture success rate were statistically higher in the CEUSLB group (p = 0.022 and p = 0.0006, respectively). There was no difference in terms of major or minor complications (p = 0.682). CEUSLB is a feasible technique that increases the diagnostic sensitivity for liver tumors developed in ACLD.

High dose vs low dose irradiation of the subventricular zone in patients with glioblastoma-a systematic review and meta-analysis.

PURPOSE: The published data indicate that the irradiation of the subventricular zone (SVZ) might play a role in the treatment of patients with glioblastoma (GBM). We aimed to determine whether radiation treatment doses (high vs low) applied to the SVZ can lead to an increase in progression free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: We undertook a systematic review and meta-analysis according to the PICOS research criteria of patients with glioblastoma which received high doses compared to low doses in order to determine if they have a better survival in observational and experimental studies. RESULTS: Our survey of the literature yielded 2573 unique records. After screening, 17 were assessed for eligibility, and in the end 8 were included in the qualitative and 4 in the quantitative analysis. Subjects who received higher doses of ipsilateral SVZ (iSVZ) irradiation had a statistically significant better PFS than those receiving lower doses (HR 0.58 [95% CI 0.42-0.82], p=0.002). Subjects receiving higher doses of contralateral SVZ (cSVZ) irradiation did not have a statistically significant better PFS than those receiving lower doses (HR =0.89 [95% CI 0.35-2.26], p=0.81). Also for OS the subjects receiving higher doses to the iSVZ did not have a statistically significant better survival than those receiving lower doses (HR =0.75 [95% CI 0.51-1.11], p=0.15). CONCLUSION: The data indicate a possible involvement of the SVZ in the onset and progression of the GBM, as well as a possible role of the SVZ in radiation therapy.

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.

Invasive bilateral breast cancer and high grade serous ovarian cancer with BRCA1-germline mutation and brainstem metastasis under PARP inhibitors.

For breast cancer patients, BRCA gene mutations are predictive of a good response to chemotherapy, but are hampered by a high risk of bilateral and synchronous or metachronous ovarian cancer. Novel therapies such as PARP-inhibitors have proven effective for BRCA1/2 mutated ovarian cancer. We present the case of a 50-year-old woman, initially diagnosed with bilateral luminal B breast cancer with BRCA1 mutation. She received neoadjuvant chemotherapy, modified radical mastectomy and bilateral adnexectomy, while subsequently identifying a synchronous advanced ovarian cancer, stage FIGO IIIC, followed by adjuvant platinum chemotherapy and external radiotherapy. After a 12 months disease-free interval a brainstem tumor was discovered, for which whole-brain radiotherapy was performed. She received 6 months of PARP-inhibitors through an early access program. With only a partial at the end of treatment, the brainstem tumor was still in progression. Due to evolution of the brain metastasis, second line chemotherapy (taxanes and Bevacizumab) was administered, with complete radiologic response. The particularity of this case resides in the coexistence of a breast and ovarian cancer in the same patient with BRCA1-germline mutation who responded to a new line of therapy - the PARP inhibitors. While being unable to perform a biopsy, we speculate that the brain metastasis in this case was most likely of breast origin.

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.

Lactate - A new frontier in the immunology and therapy of prostate cancer.

Prostate cancer, one of the most common male malignancies with an increasing incidence in the recent years, requires the development of new methods of treatment. One of the most debated subjects is the tumor-associated macrophages (TAM). Although, the pathophysiological mechanisms are still a subject of intense research, TAM acts as procarcinogenic factors. It was also demonstrated that hypoxia-inducible factor 1 (HIF1) induces the expression of TAM genes involved in prostate carcinogenesis. Furthermore, it should be noted that the stromal extracellular lactate, the result of tumoral glycolysis process is one of the HIF1 activators. In addition, lactate inhibits the differentiation of monocytes and dendritic cells and also induces the inactivation of the cytotoxic T-lymphocytes. Through an analysis of recent studies, we conclude that lactate is a vital component of several ways of modulating the immune response at the stromal prostatic adenocarcinoma including TAM activation and cytotoxic T lymphocytes immunosuppression. Our review focuses on the impact of lactate on prostatic adenocarcinoma progression in terms of its immunology, and how this influences the therapy of this condition and the clinical outcome.

Phase III Study Comparing a Reduced Dose of Cabazitaxel (20 mg/m2) and the Currently Approved Dose (25 mg/m2) in Postdocetaxel Patients With Metastatic Castration-Resistant Prostate Cancer-PROSELICA.

Purpose Cabazitaxel 25 mg/m2 (C25) significantly improved overall survival (OS) versus mitoxantrone ( P < .001) in postdocetaxel patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase III TROPIC study. The phase III PROSELICA study ( ClinicalTrials.gov identifier: NCT01308580) assessed the noninferiority of cabazitaxel 20 mg/m2 (C20) versus C25 in postdocetaxel patients with mCRPC. Methods Patients were stratified by Eastern Cooperative Oncology Group performance status, measurability of disease per Response Evaluation Criteria in Solid Tumors (RECIST), and region, and randomly assigned to receive C20 or C25. To claim noninferiority of C20 (maintenance of ≥ 50% of the OS benefit of C25 v mitoxantrone in TROPIC) with 95% confidence level, the upper boundary of the CI of the hazard ratio (HR) for C20 versus C25 could not exceed 1.214 under a one-sided 98.89% CI after interim analyses. Secondary end points included progression-free survival, prostate-specific antigen (PSA), tumor and pain responses and progression, health-related quality of life, and safety. Results Overall, 1,200 patients were randomly assigned (C20, n = 598; C25, n = 602). Baseline characteristics were similar in both arms. Median OS was 13.4 months for C20 and 14.5 months for C25 (HR, 1.024). The upper boundary of the HR CI was 1.184 (less than the 1.214 noninferiority margin). Significant differences were observed in favor of C25 for PSA response (C20, 29.5%; C25, 42.9%; nominal P < .001) and time to PSA progression (median: C20, 5.7 months; C25, 6.8 months; HR for C20 v C25, 1.195; 95% CI, 1.025 to 1.393). Health-related quality of life did not differ between cohorts. Rates of grade 3 or 4 treatment-emergent adverse events were 39.7% for C20 and 54.5% for C25. Conclusion The efficacy of cabazitaxel in postdocetaxel patients with mCRPC was confirmed. The noninferiority end point was met; C20 maintained ≥ 50% of the OS benefit of C25 versus mitoxantrone in TROPIC. Secondary efficacy end points favored C25. Fewer adverse events were observed with C20.

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.

Prospective comparison between real time contrast enhanced and conventional ultrasound guidance in percutaneous biopsies of liver tumors.

AIMS: The performance of percutaneous echo-guided biopsy in the hepatic tumoral diagnosis is limited (90% sensitivity) by several factors, among which tumor characteristics (type, size, and location) play an important role. Contrast enhanced ultrasound guided percutaneous biopsy (CEUS-PLB) is a new developed technique aimed at increasing the accuracy of percutaneous biopsies. The objective of our study was to evaluate the feasibility and performance of CEUS as a guiding method in performing liver biopsy (PLB). MATERIAL AND METHODS: One hundred and seventy one patients with liver tumors referred to the ultrasound department for LB were prospectively included in the study. PLB was performed with CEUS guidance in 90 patients (46 in patients with and 44 in patients without liver cirrhosis), in the remaining 81 (37 in patients with liver cirrhosis and 44 in patients without) with conventional US guidance. The lesions in the CEUS -PLB group were larger than those in the US-LB group (mean diameter 7.73 cm vs. 6.11 cm, p>0.05). In both groups the lesions were further divided in: a) lesions on cirrhosis; b) poorly visualized tumors; c) large tumors (>6 cm); d) cystic tumors; e) recurrences after ablation; and f) portal vein thrombosis. RESULTS: Real time CEUS-PLB was technically successful in 84 of the 86 procedures (97.6% technical success rate). The rate of successful single puncture attempt in CEUS-PLB (43.02%) was higher than in the US-PLB group (23.4%) (p<0.05). The sensitivity of LB was significantly higher in the CEUS-PLB group than in the conventional US-LB group for all lesions (96.5% vs. 81.48%, p<0.05), for lesions on liver cirrhosis (95.2% vs. 75%, p<0.05), for large (> 6 cm) (97.8% vs. 82%, p<0.05), and for poorly visible lesions (100 vs. 66.6%, p=0.029). The patients with inconclusive pathological results after conventional guided LB were then biopsied with CEUS guidance. In all cases the final diagnosis could be established. One major complication occurred in each group (p>0.05). CONCLUSIONS: Percutaneous LB performed with CEUS guidance is a feasible and safe technique. It significantly improves the overall sensitivity of the procedure especially in patients with large lesions and in those poorly visualized on conventional ultrasound.

Contrast enhanced ultrasound of renal masses. A reappraisal of EFSUMB recommendations and possible emerging applications.

The main imagistic method for characterization of renal lesions is contrast enhanced computed tomography (CECT). Disadvantages of CECT are a contrast-induced nephropathy in patients with renal impairment, allergic reactions and high costs. Contrast-enhanced ultrasound (CEUS) evaluation of hepatic and non-hepatic lesions is a relatively new, but increasingly utilised, diagnostic method. In 2011 the European Federation of Societies of Ultrasound in Medicine and Biology (EFSUMB) updated the Guidelines and Recommendations on the Clinical Practice of CEUS and included in the recommendation the renal pathology. However, there are several possible new indications that have not been discussed (pyelocaliceal masses and renal vein thrombosis) and several issues that remain controversial such as the differentiation of benign and malignant tumours or the differentiation of lymphoma and metastasis. This study aims to review literature data, as well as reveal the latest findings in the field of renal CEUS.

Brachytherapy next generation: robotic systems.

In a field dominated by external beam radiation therapy (EBRT), both the therapeutic and technical possibilities of brachytherapy (BT) are underrated, shadowed by protons and intensity modulated radiotherapy. Decreasing expertise and indications, as well as increasing lack of specific BT training for radiation therapy (RT) residents led to the real need of shortening its learning curve and making it more popular. Developing robotic BT devices can be a way to mitigate the above issues. There are many teams working at custom-made robotic BT platforms to perfect and overcome the limitations of the existing systems. This paper provides a picture of the current state-of-the-art in robotic assisted BT, as it also conveys the author's solution to the problem, a parallel robot that uses CT-guidance.