Heme catabolism by tumor-associated macrophages controls metastasis formation.

Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1-CSF1R-C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1+ myeloid subgroup as a new antimetastatic target and prognostic blood marker.

Tolerability of Eribulin and correlation between polymorphisms and neuropathy in an unselected population of female patients with metastatic breast cancer: results of the multicenter, single arm, phase IV PAINTER study.

BACKGROUND: Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses on prolonging patients' (pts) overall survival (OS) and improving their quality of life. Eribulin is a microtubule inhibitor that increases OS in pre-treated MBC pts. The most common adverse events (AEs) are asthenia, neutropenia and peripheral neuropathy (PN). METHODS: PAINTER is a single arm, phase IV study, aimed at evaluating the tolerability of eribulin in MBC pts. Secondary objectives were the description of treatment efficacy and safety, the assessment of the incidence and severity of PN and its association with genetic polymorphisms. Genomic DNA was isolated from blood samples and 15 Single Nucleotide Polymorphisms (SNPs) were genotyped by Taqman specific assays. The association between PN and SNPs were evaluated by Fisher exact test. RESULTS: Starting from May 2014 until June 2018 180 pts were enrolled in this study by 20 Italian centers. 170 of these pts could be evaluated for efficacy and toxicity and 159 for polymorphisms analysis. The median age of pts was 60 years old and the biological subtypes were luminal type (64.7%), Her2 positive (18.3%) and triple negative (17%). Pts were pretreated with a median of 5 lines for MBC. The median follow up of this study was 15.4 months with a median number of 4.5 cycles administered (minimum-maximum 1-23). The median overall survival was 12 months. 48.8% of pts experienced a dose reduction, mainly for neutropenia (23.9%) and liver toxicity (12%). 65 pts (38.2%) reported at least one severe toxicity. Neutropenia and neurotoxicity were the most frequent severe AEs (15.3% and 14.7%, respectively); other reported toxicities were osteo-muscular, abdominal or tumor site pain (19.4%), liver toxicity (6.6%), pulmonary toxicity (6.5%) and dermatological toxicity (3.6%). Among the 15 evaluated SNPs, an association with PN was found for rs2233335 and rs7214723. CONCLUSIONS: Eribulin is a well-tolerated treatment option in MBC. Schedule and dosage modifications were common, but toxicity rarely led to treatment discontinuation. SNPs rs2233335 (G/T and T/T) in the NDRG1 gene and rs7214723 (CC and CT) in the CAMKK1 gene were associated with PN. These findings, if validated, could allow a tailored treatment with eribulin in cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02864030.

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer.

BACKGROUND: Previous findings showed that cediranib-olaparib increased PFS in women with recurrent platinum-sensitive ovarian cancer compared to olaparib alone. METHODS: BAROCCO trial randomized 123 patients: 80mg/m2 paclitaxel weekly up to 24 weeks (control), olaparib 300mg tablets twice daily together with 20mg cediranib daily (continuous schedule) or with 20mg cediranib 5 days/week (intermittent schedule) until progression. The primary objective was the PFS comparison between each experimental arm and the control (alpha one-sided 5%; power 80%; HR 0.5). RESULTS: The median platinum-free interval was 1.9 months, 60% of patients had been pretreated with 3 or more chemotherapy lines. Median PFS for paclitaxel, the continuous, and the intermittent schedules were 3.1, 5.6, and 3.8 months. The HR for PFS in the continuous arm vs control was 0.76 (90% CI: 0.50-1.14, p = 0.265). The HR for PFS in the intermittent arm vs control was 1.03 (90% CI: 0.68-1.55, p = 0.904). Treatment was discontinued due to adverse events in 15%, 20%, and 5% of patients in the control, continuous and intermittent arms. Grade ≥ 3 anemia and diarrhea and hypertension of any grade occurred only in the experimental arms, and peripheral neuropathies and alopecia only in the control arm. Five serious adverse drug reactions occurred and two were fatal: one in the control and one in the continuous arm. CONCLUSIONS: The combination of cediranib-olaparib was not superior to chemotherapy in terms of PFS in heavily pretreated platinum-resistant ovarian cancer patients. However, this oral doublet, is active and may offer a non-chemotherapy option in this difficult to treat population. CLINICAL TRIAL IDENTIFICATION: IRFMN-OVA-7289, EudraCT: 2016-003964-38, NCT03314740.

Duration of Adjuvant Chemotherapy for Stage III Colon Cancer.

BACKGROUND: Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures. METHODS: We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12. RESULTS: After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority). CONCLUSIONS: Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials.

BACKGROUND: A prospective, pooled analysis of six randomised phase 3 trials was done to investigate disease-free survival regarding non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer; non-inferiority was not shown. Here, we report the final overall survival results. METHODS: In this prospective, pooled analysis of six randomised phase 3 trials, we included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-1 recruited between June 20, 2007, and Dec 31, 2015, across 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials, who started any treatment (modified intention-to-treat). Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or capecitabine and oxaliplatin (CAPOX) in different doses and methods every 3 weeks, at the treating physician's discretion. The primary endpoint was disease-free survival (time to relapse, secondary colorectal primary tumour, or death due to all causes), and overall survival (time to death due to all causes) was the prespecified secondary endpoint. The non-inferiority margin for overall survival was set as a hazard ratio (HR) of 1·11. Pre-planned subgroup analyses included regimen and risk group. Non-inferiority was declared if the one-sided false discovery rate adjusted (FDRadj) p value was less than 0·025. FINDINGS: With median follow-up of 72·3 months (IQR 72·2-72·5), 2584 deaths among 12 835 patients were observed. 5064 (39·5%) patients received CAPOX and 7771 (60·5%) received FOLFOX. 5-year overall survival was 82·4% (95% CI 81·4-83·3) with 3 months of therapy and 82·8% (81·8-83·8) with 6 months of therapy (HR 1·02 [95% CI 0·95-1·11]; non-inferiority FDRadj p=0·058). For patients treated with CAPOX, 5-year overall survival was 82·1% (80·5-83·6) versus 81·2% (79·2-82·9; HR 0·96 [0·85-1·08]); non-inferiority FDRadj p=0·033), and for patients treated with FOLFOX 5-year overall survival was 82·6% (81·3-83·8) and 83·8% (82·6-85·0; HR 1·07 [0·97-1·18]; non-inferiority FDRadj p=0·34). Updated disease-free survival results confirmed previous findings (HR 1·08 [95% CI 1·02-1·15]; non-inferiority FDRadj p=0·25). Data on adverse events were not further recorded. INTERPRETATION: Non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0·4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration. FUNDING: US National Cancer Institute.

COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study.

BACKGROUND: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies. METHODS: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data. FINDINGS: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death. INTERPRETATION: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference. FUNDING: None.

Diagnostic and prognostic values of PBMC proteins in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease for which there are no validated biomarkers. Previous exploratory studies have identified a panel of candidate protein biomarkers in peripheral blood mononuclear cells (PBMCs) that include peptidyl-prolyl cis-trans isomerase A (PPIA), heat shock cognate protein 71 kDa (HSC70), heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) and TDP-43. It has also been found that PPIA plays a key role in the assembly and dynamics of ribonucleoprotein (RNP) complexes and interacts with TDP-43. Its absence accelerates disease progression in a SOD1 mouse model of ALS, and low levels of PPIA in PBMCs are associated with early-onset ALS. However, the diagnostic and prognostic values of PPIA and the other candidate protein biomarkers have not been established. We analyzed the PBMC proteins in a well-characterized cohort of ALS patients (n=93), healthy individuals (n=104) and disease controls (n=111). We used a highly controlled sample processing procedure that implies two-step differential detergent fractionation. We found that the levels of the selected PBMC proteins in the soluble and insoluble fraction, combined, have a high discriminatory power for distinguishing ALS from controls, with PPIA, hnRNPA2B1 and TDP-43 being the proteins most closely associated with ALS. We also found a shift toward increased protein partitioning in the insoluble fraction in ALS and this correlated with a worse disease phenotype. In particular, low PPIA soluble levels were associated with six months earlier death. In conclusion, PPIA is a disease modifier with prognostic potential. PBMC proteins indicative of alterations in protein and RNA homeostasis are promising biomarkers of ALS, for diagnosis, prognosis and patient stratification.

Early progression of disease predicts shorter survival in MALT lymphoma patients receiving systemic treatment.

Early progression of disease (POD) within two years from diagnosis is linked with poor overall survival (OS) in follicular lymphoma but its prognostic role is less clear in extranodal marginal zone B-cell lymphoma (EMZL). We sought to identify prognostic factors associated with early POD and to determine whether is associated with inferior OS. We analyzed the impact of early POD in the IELSG19 clinical trial dataset (training set of 401 patients randomly assigned to chlorambucil or rituximab or chlorambucil plus rituximab). Reproducibility was examined in a validation set of 287 patients who received systemic treatment. In both sets, we excluded from the analysis the patients who, within 24 months from treatment start, died without progression or were lost to follow-up without prior progression. OS was calculated from progression in patients with early POD and from 24 months after start of treatment in those without (reference group). Early POD was observed in 69 of the 384 (18%) evaluable patients of the IELSG19 study. Patients with high-risk MALT-IPI were more likely to have early POD (p=0.006). The 10-year OS rate was 64% in the early POD group and 85% in the reference group (HR= 2.42, 95%CI, 1.35-4.34; log-rank P=0.002). This prognostic impact was confirmed in the validation set, in which early POD was observed in 64 out of 224 (29%) evaluable patients with 10-year OS rate of 48% in the early POD group and 71% in the reference group (HR= 2.15, 95%CI, 1.19-3.90; log-rank P=0.009). In patients with EMZL who received front-line systemic treatment, early POD is associated with poorer survival and may represent a useful endpoint in future prospective clinical trials.

Correction to: Standard (8 weeks) vs long (12 weeks) timing to minimally-invasive surgery after NeoAdjuvant Chemoradiotherapy for rectal cancer: a multicenter randomized controlled parallel group trial (TiMiSNAR).

Following publication of the original article [1], the authors reported that the family name of the author, Ludovica Baldari, was misspelled.

Multicenter, randomised, open-label, non-comparative phase 2 trial on the efficacy and safety of the combination of bevacizumab and trabectedin with or without carboplatin in women with partially platinum-sensitive recurrent ovarian cancer.

BACKGROUND: Trabectedin, in addition to its antiproliferative effect, can modify the tumour microenvironment and this could be synergistic with bevacizumab. The efficacy and safety of trabectedin and bevacizumab ± carboplatin have never been investigated. METHODS: In this phase 2 study, women progressing between 6 and 12 months since their last platinum-based therapy were randomised to Arm BT: bevacizumab, trabectedin every 21 days, or Arm BT+C: bevacizumab, trabectedin and carboplatin every 28 days, from cycles 1 to 6, then trabectedin and bevacizumab as in Arm BT. Primary endpoints were progression-free survival rate (PFS-6) and severe toxicity rate (ST-6) at 6 months, assuming a PFS-6 ≤35% for BT and ≤40% for BT+C as not of therapeutic interest and, for both arms, a ST-6 ≥ 30% as unacceptable. RESULTS: BT+C (21 patients) did not meet the safety criteria for the second stage (ST-6 45%; 95%CI: 23%-69%) but PFS-6 was 85% (95%CI: 62%-97%). BT (50 patients) had 75% PFS-6 (95%CI: 60%-87%) and 16% ST-6 (95%CI 7%-30%). CONCLUSIONS: BT compared favourably with other platinum- and non-platinum-based regimens. The combination with carboplatin needs to be assessed further in a re-modulated safer schedule to confirm its apparent strong activity. CLINICAL TRIAL REGISTRATION: NCT01735071 (Clinicaltrials.gov).

HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer.

BACKGROUND: HER2 amplification is detected in 3% of patients with colorectal cancer (CRC), making tumors in the metastatic setting vulnerable to double pharmacological HER2 blockade. Preclinical findings show that it also might impair response to anti-epidermal growth factor receptor (EGFR) treatment. SUBJECTS AND METHODS: Patients with KRAS exon 2 wild-type metastatic CRC underwent molecular screening of HER2 positivity by HERACLES criteria (immunohistochemistry 3+ or 2+ in ≥50% of cells, confirmed by fluorescence in situ hybridization). A sample of consecutive HER2-negative patients was selected as control. A regression modeling strategy was applied to identify predictors explaining the bulk of HER2 positivity and the association with response to previous anti-EGFR treatment. RESULTS: From August 2012 to April 2018, a total of 100 HER2-positive metastatic CRC tumors were detected out of 1,485 KRAS exon 2 wild-type screened patients (6.7%). HER2-positive patients show more frequently lung metastases (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.15-3.61; p = .014) and higher tumor burden (OR, 1.48; 95% CI, 1.10-2.01; p = .011), and tumors were more likely to be left sided (OR, 0.50; 95% CI, 0.22-1.11; p = .088). HER2-positive patients who received treatment with anti-EGFR agents (n = 79) showed poorer outcome (objective response rate, 31.2% vs. 46.9%, p = .031; progression-free survival, 5.7 months vs. 7 months, p = .087). CONCLUSION: Testing for HER2 should be offered to all patients with metastatic CRC because the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Patients with HER2-amplified metastatic CRC are less likely to respond to anti-EGFR therapy. IMPLICATIONS FOR PRACTICE: Patients with HER2-amplified/overexpressed metastatic colorectal cancer (mCRC) harbor a driver actionable molecular alteration that has been shown in preclinical models to hamper efficacy of the anti-epidermal growth factor receptor (EGFR) targeted therapies. The present study confirmed that this molecular feature was associated with worse objective tumor response and shorter progression-free survival in response to previous anti-EGFR therapies. Moreover, it was found that the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Therefore, HER2 status assessment should be included in the molecular diagnostic workup of all mCRC for speedy referral to clinical trials encompassing HER2-targeted double blockade independently of previous anti-EGFR treatment.

A MALT lymphoma prognostic index.

There are no widely accepted prognostic indices for extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). This study aimed to develop and validate a specific prognostic tool to personalize and optimize treatment of patients with MALT lymphoma. A prognostic index was built by Cox regression (stepwise selection) using data from 401 patients enrolled in the international randomized International Extranodal Lymphoma Study Group 19 (IELSG-19) trial (NCT 00210353). A validation set, including 633 patients, was obtained by merging 3 independent cohorts of MALT lymphoma patients. The 3 individual features maintaining the greatest prognostic significance for event-free survival (EFS, the main endpoint of the IELSG-19 trial) were age ≥70 years (hazard ratio [HR], 1.72; 95% confidence interval [CI], 1.26-2.33), Ann Arbor stage III or IV (HR, 1.79; 95% CI ,1.35-2.38), and an elevated lactate dehydrogenase level (HR, 1.87; 95% CI, 1.27-2.77). The prognostic index (MALT-IPI) constructed using these 3 parameters identified 3 groups: low, intermediate, and high risk (corresponding to the presence of 0, 1, or ≥2 of these factors, respectively). The 5-year EFS rates in the low-, intermediate-, and high-risk groups were 70%, 56%, and 29%, respectively. The MALT-lymphoma International Prognostic Index (MALT-IPI) also significantly discriminated between patients with different progression-free, overall, and cause-specific survival. The prognostic utility was retained in gastric and nongastric lymphomas, in each treatment arm (chlorambucil, rituximab, and rituximab plus chlorambucil), and was confirmed in the validation set. The new index, MALT-IPI, is a simple, accessible, and effective tool to identify MALT lymphoma patients at risk of poor outcomes. It may help define appropriate treatment approaches for individual patients.

Standard (8 weeks) vs long (12 weeks) timing to minimally-invasive surgery after NeoAdjuvant Chemoradiotherapy for rectal cancer: a multicenter randomized controlled parallel group trial (TiMiSNAR).

BACKGROUND: The optimal timing of surgery in relation to chemoradiation is still controversial. Retrospective analysis has demonstrated in the recent decades that the regression of adenocarcinoma can be slow and not complete until after several months. More recently, increasing pathologic Complete Response rates have been demonstrated to be correlated with longer time interval. The purpose of the trial is to demonstrate if delayed timing of surgery after neoadjuvant chemoradiotherapy actually affects pathologic Complete Response and reflects on disease-free survival and overall survival rather than standard timing. METHODS: The trial is a multicenter, prospective, randomized controlled, unblinded, parallel-group trial comparing standard and delayed surgery after neoadjuvant chemoradiotherapy for the curative treatment of rectal cancer. Three-hundred and forty patients will be randomized on an equal basis to either robotic-assisted/standard laparoscopic rectal cancer surgery after 8 weeks or robotic-assisted/standard laparoscopic rectal cancer surgery after 12 weeks. DISCUSSION: To date, it is well-know that pathologic Complete Response is associated with excellent prognosis and an overall survival of 90%. In the Lyon trial the rate of pCR or near pathologic Complete Response increased from 10.3 to 26% and in retrospective studies the increase rate was about 23-30%. These results may be explained on the relationship between radiation therapy and tumor regression: DNA damage occurs during irradiation, but cellular lysis occurs within the next weeks. Study results, whether confirmed that performing surgery after 12 weeks from neoadjuvant treatment is advantageous from a technical and oncological point of view, may change the current pathway of the treatment in those patient suffering from rectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT3465982.

Multicenter, single arm, phase II trial on the efficacy of ortataxel in recurrent glioblastoma.

BACKGROUND AND PURPOSE: Glioblastoma (GBM) is the most aggressive and frequent subtype of all malignant gliomas. At the time of recurrence, therapeutic options are lacking. Ortataxel, a second-generation taxane was reported to be effective in pre-clinical and phase I clinical studies. The aim of this study was to evaluate a potential therapeutic activity of ortataxel in patients with GBM recurring after surgery and first line treatment. METHODS: In this phase II study, according to a two stage design, adult patients with histologically confirmed GBM in recurrence after surgery or biopsy, standard radiotherapy and chemotherapy with temozolomide were considered eligible. Patients included were treated with ortataxel 75 mg/m2 i.v. every 3 weeks until disease progression. The primary objective of the study was to evaluate the activity of ortataxel in terms of progression free survival (PFS) at 6 months after the enrollment. PFS, overall survival at 9 months after the enrollment, objective response rate, compliance and safety were evaluated as secondary endpoints. RESULTS: Between Nov 26, 2013 and Dec 12, 2015, 40 patients were recruited across six centres. The number of patients alive and free from progression at 6 months after the enrollment, observed in the first stage was four (11.4%), out of 35 patients included in the analysis, below the minimum number of events (7 out of 33) required to continue the study with the second stage The most important toxicities were neutropenia and hepatotoxicity that occurred in 13.2% of patients and leukopenia that occurred in 15.8% of patients. CONCLUSION: Overall ortataxel treatment fail to demonstrate a significant activity in recurrent GBM patients. However in a limited number of patients the drug produced a benefit that lasted for a long time. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT01989884.

Gadoxetate Disodium-Enhanced MR Cholangiography for Evaluation of Biliary-Enteric Anastomoses: Added Value Beyond Conventional T2-Weighted Images.

OBJECTIVE. The objective of our study was to evaluate image quality and reader confidence in MR cholangiography of bile ducts using conventional T2-weighted MR cholangiography alone in comparison with T2-weighted MR cholangiography and gadoxetate disodium-enhanced MR cholangiography in a series of patients with biliary-enteric anastomosis (BEA). SUBJECTS AND METHODS. Fifty patients with BEA and clinically and sonographically suspected complications underwent 1.5-T MRI. After acquisition of T1- and T2-weighted images, conventional MR cholangiography was performed using 3D fast relaxation fast spin-echo (FRFSE) and single-shot fast spin-echo (SSFSE) T2-weighted sequences (image set 1). In each patient, a 3D fat-suppressed Liver Acquisition with Volume Acceleration (LAVA) sequence was performed before and 15, 20, 25, 30, and 40 minutes after IV administration of 0.1 mL/kg of gadoxetate disodium (Primovist) (image set 2). Two radiologists in consensus evaluated image quality in the anatomic segments of the biliary tract and recorded diagnostic confidence scores for image set 1 alone and image sets 1 and 2 together. MRI findings were compared with postsurgical specimen if surgery was performed, conventional cholangiography, or 12 months of imaging follow-up. RESULTS. A significant improvement in image quality for visualization of all biliary segments was found using gadoxetate disodium-enhanced MR cholangiography in comparison with T2-weighted MR cholangiography alone. Readers judged diagnostic confidence of image set 1 alone and image sets 1 and 2 together as very confident in three and 37 cases, confident in 30 and 11, not confident in 14 and one, and not confident at all in three and 1, respectively. Concordance between image set 1 alone and image sets 1 and 2 together and the reference standard results was present in 23 of 50 cases (46%) and 47 of 50 cases (94%), respectively (p < 0.0001). CONCLUSION. Gadoxetate disodium-enhanced MR cholangiography can improve image quality for visualization of the biliary tract and further enhanced the diagnostic performance of conventional T2-weighted MR cholangiography in the evaluation of patients with BEA.

Assessment of proportional hazard assumption in aggregate data: a systematic review on statistical methodology in clinical trials using time-to-event endpoint.

BACKGROUND: The evaluation of the proportional hazards (PH) assumption in survival analysis is an important issue when Hazard Ratio (HR) is chosen as summary measure. The aim is to assess the appropriateness of statistical methods based on the PH assumption in oncological trials. METHODS: We selected 58 randomised controlled trials comparing at least two pharmacological treatments with a time-to-event as primary endpoint in advanced non-small-cell lung cancer. Data from Kaplan-Meier curves were used to calculate the relative hazard at each time point and the Restricted Mean Survival Time (RMST). The PH assumption was assessed with a fixed-effect meta-regression. RESULTS: In 19% of the trials, there was evidence of non-PH. Comparison of treatments with different mechanisms of action was associated (P = 0.006) with violation of the PH assumption. In all the superiority trials where non-PH was detected, the conclusions using the RMST corresponded to that based on the Cox model, although the magnitude of the effect given by the HR was systematically greater than the one from the RMST ratio. CONCLUSION: As drugs with new mechanisms of action are being increasingly employed, particular attention should be paid on the statistical methods used to compare different types of agents.

A phase II randomised (calibrated design) study on the activity of the single-agent trabectedin in metastatic or locally relapsed uterine leiomyosarcoma.

BACKGROUND: Patients with recurrent/metastatic uterine leiomyosarcoma (U-LMS) have a dismal prognosis. This phase II study aims to evaluate trabectedin efficacy and safety in advanced U-LMS. METHODS: Eligible patients had received ≥ one line of chemotherapy. Gemcitabine ± docetaxel naive patients were randomised to Arm A: trabectedin 1.3 mg/m2 or calibration Arm B: gemcitabine 900 mg/m2 and docetaxel 75 mg/m2. Patients who had already received gemcitabine ± docetaxel directly entered Arm A. Primary end-point: 6-month progression-free rate (PFS-6). The null hypothesis that the true PFS-6 = 14% was tested against a one-sided alternative. This design yielded a 5% type I error rate and 90% power when the true PFS-6 is 25%. RESULTS: Overall, 126 patients entered Arm A (45 from randomisation and 81 directly) and 42 Arm B. Arm A patients characteristics: median age = 57; ≥2 previous chemotherapy lines = 37.4%; metastatic disease = 93%. The study met the condition for trabectedin activity: PFS-6 = 35.2% (95% CI: 26.2-45). No difference in PFS by the number of previous chemotherapy lines emerged. Median OS = 20.6 months (IQR: 8-36.4). In Arm B, the PFS-6 = 51.5% (95% CI: 33.5-69.2). No toxic deaths occurred. In Arm A, only 4 patients interrupted treatment for toxicity. CONCLUSIONS: Trabectedin is active and well tolerated, retaining similar efficacy across one to three previous lines of chemotherapy.

Brain Gliomas: Multicenter Standardized Assessment of Dynamic Contrast-enhanced and Dynamic Susceptibility Contrast MR Images.

Purpose To evaluate the feasibility of a standardized protocol for acquisition and analysis of dynamic contrast material-enhanced (DCE) and dynamic susceptibility contrast (DSC) magnetic resonance (MR) imaging in a multicenter clinical setting and to verify its accuracy in predicting glioma grade according to the new World Health Organization 2016 classification. Materials and Methods The local research ethics committees of all centers approved the study, and informed consent was obtained from patients. One hundred patients with glioma were prospectively examined at 3.0 T in seven centers that performed the same preoperative MR imaging protocol, including DCE and DSC sequences. Two independent readers identified the perfusion hotspots on maps of volume transfer constant (Ktrans), plasma (vp) and extravascular-extracellular space (ve) volumes, initial area under the concentration curve, and relative cerebral blood volume (rCBV). Differences in parameters between grades and molecular subtypes were assessed by using Kruskal-Wallis and Mann-Whitney U tests. Diagnostic accuracy was evaluated by using receiver operating characteristic curve analysis. Results The whole protocol was tolerated in all patients. Perfusion maps were successfully obtained in 94 patients. An excellent interreader reproducibility of DSC- and DCE-derived measures was found. Among DCE-derived parameters, vp and ve had the highest accuracy (are under the receiver operating characteristic curve [Az] = 0.847 and 0.853) for glioma grading. DSC-derived rCBV had the highest accuracy (Az = 0.894), but the difference was not statistically significant (P > .05). Among lower-grade gliomas, a moderate increase in both vp and rCBV was evident in isocitrate dehydrogenase wild-type tumors, although this was not significant (P > .05). Conclusion A standardized multicenter acquisition and analysis protocol of DCE and DSC MR imaging is feasible and highly reproducible. Both techniques showed a comparable, high diagnostic accuracy for grading gliomas. © RSNA, 2018 Online supplemental material is available for this article.