Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZ-RTE-01 trial protocol.

BACKGROUND: Despite multimodality treatments including neurosurgery, radiotherapy and chemotherapy, glioblastoma (GBM) prognosis remains poor. GBM is classically considered as a radioresistant tumor, because of its high local recurrence rate, inside the irradiation field. The development of new radiosensitizer is crucial to improve the patient outcomes. Pre-clinical data showed that Poly (ADP-ribose) polymerase inhibitors (PARPi) could be considered as a promising class of radiosensitizer. The aim of this study is to evaluate Olaparib, a PARPi, as radiosensitizing agent, combined with the Stupp protocol, namely temozolomide (TMZ) and intensity modulated radiotherapy (IMRT) in first line treatment of partially or non-resected GBM. METHODS: The OLA-TMZ-RTE-01 study is a multicenter non-randomized phase I/IIa trial including unresectable or partially resectable GBM patients, from 18 to 70 years old. A two-step dose-escalation phase I design will first determine the recommended phase 2 dose (RP2D) of olaparib, delivered concomitantly with TMZ plus conventional irradiation for 6 weeks and as single agent for 4 weeks (radiotherapy period), and second, the RP2D of olaparib combined with adjuvant TMZ (maintenance period). Phase IIa will assess the 18-month overall survival (OS) of this combination. In both phase I and IIa separately considered, the progression-free survival, the objective response rate, the neurocognitive functions of patients, emotional disorders among caregivers, the survival without toxicity, degradation nor progression, the complications onset and the morphologic and functional MRI (magnetic resonance imaging) parameters will be also assessed as secondary objectives. Ancillary objectives will explore alteration of the DNA repair pathways on biopsy tumor, proton magnetic resonance spectroscopy parameters to differentiate tumor relapse and radionecrosis, and an expanded cognition evaluation. Up to 79 patients will be enrolled: 30 patients in the phase I and 49 patients in the phase IIa. DISCUSSION: Combining PARP inhibitors, such as olaparib, with radiotherapy and chemotherapy in GBM may improve survival outcomes, while sparing healthy tissue and preserving neurocognitive function, given the replication-dependent efficacy of olaparib, and the increased PARP expression in GBM as compared to non-neoplastic brain tissue. Ancillary studies will help to identify genetic biomarkers predictive of PARPi efficacy as radiosensitizer. TRIAL REGISTRATION: NCT03212742 , registered June, 7, 2017. Protocol version: Version 2.2 dated from 2017/08/18.

Optimisation of chemotherapy prescription and preparation in an ambulatory unit: Validation of the OPTIMA program.

OBJECTIVE: We implemented the two-step OPTIMA program to anticipate chemotherapy prescription which aims to assess the discrepancy rate between anticipated and real prescription and its impact on waiting time and quality of care. METHODS: This prospective study included cancer patients receiving any intravenous chemotherapy. The OPTIMA program consists in a nurse phone call and a blood sample two days before the planned treatment. Collected information and biological results were used by a physician to issue a non-effective (step 1) or effective (step 2) anticipated prescription the day before the consultation. The real prescription was given as usual by another physician on the day of the consultation. Waiting time was collected, and patients' satisfaction with care was assessed with the OUT-PATSAT35 questionnaire. RESULTS: Respectively, 540 and 979 consultations (283 and 294 patients) were analysed in both steps. The discrepancy rate was 8.7% (step 1). In routine practice, the OPTIMA program (step 2) reduced patients' waiting time (median time 55 vs. 95 min, p < 0.001). A high general care satisfaction score was observed in both steps (80.7% and 80.2%). CONCLUSIONS: This anticipation program demonstrated the accuracy of chemotherapy prescription, whatever the regimen and cancer site, and its impact on waiting time optimisation.

Oncologic Outcomes of Adjuvant versus Salvage Radiotherapy after Prostatectomy.

INTRODUCTION: The benefit of adjuvant radiotherapy (AR) or salvage radiotherapy (SR) after prostatectomy is still unclear. We wanted to compare both types of radiotherapy after prostatectomy in terms of oncological and functional results. METHODS: We included 173 patients treated at a single center between January 2005 and December 2008. All patients were treated with the same radiotherapy protocol (3D conformal radiotherapy accelerator 6 mV, 66 GY). AR was defined as radiotherapy initiated in a patient with a PSA level <0.2 ng/mL after prostatectomy otherwise it was defined as SR. No patients received neoadjuvant therapy prior to prostatectomy (whether hormone therapy or chemotherapy). Patients in the SR group had a PSA level ≥0.2 ng/mL during the treatment in accordance with the Phoenix criteria. The lymph nodes were irradiated if the patient had no lymph node dissection and if the risk of nodal involvement was >10%. Both groups were compared in terms of biological progression-free, metastasis-free, and overall survival (OS) using log-rank tests. Moreover, acute and late urinary and gastrointestinal toxicity were also compared. RESULTS: One hundred and fifty-seven patients underwent an open retropubic prostatectomy whereas 16 underwent a laparoscopy (6 subperitoneal and 10 transperitoneal). Eighty-six patients had AR with a median time of 6.7 months after surgery and 87 had SR with a median time of 21.4 months after surgery. Median follow-up was 6.7 years. Metastasis-free survival (MFS) was better in the AR than in the SR group (p = 0.01, 6-year MFS 95 and 89%, respectively). OS was also better in the AR than in the SR group (p = 0.02, 6-year OS 100 vs. 95%, respectively). AR was associated with better survival with no biochemical recurrence (85 vs. 63%, p < 0.00001). There was no significant difference between groups for acute or late urinary or gastrointestinal toxicity. CONCLUSION: Our study suggests that patients treated by AR have better results in terms of OS, disease-specific survival, survival without metastatic recurrence, and survival without biochemical recurrence compared with SR. Toxicity was comparable between both groups.

Haemoglobin level increase as an efficacy biomarker during axitinib treatment for metastatic renal cell carcinoma: a retrospective study.

BACKGROUND: Axitinib is used after failure of first line treatment for metastatic renal cell carcinoma (mRCC). A known side effect is the increase of haemoglobin level (HbL) during treatment with a suspected correlation with better outcome. Our objective was to examine whether HbL increase during the first three months of axitinib treatment is associated with better prognosis. METHODS: Retrospective multicentre analysis including patients with mRCC treated with axitinib for at least three months from 2012 to 2014. Progression-free survival (PFS) was analysed by a Cox model according to gender, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score, high blood pressure (hBP), and maximum increase in HbL within the first three months of treatment. RESULTS: Ninety-eight patients were analysed (71% men; median age at treatment initiation: 62 years; IMDC: 24%, 50%, and 26% in the favourable, intermediate, and poor-risk group, respectively). Patients received axitinib for a median of 8 months. During the first three months, the median increase of HbL was +2.3 g/dL (-1.1; 7.2). Fifty-six (57%) patients developed hBP. In multivariate analysis, after adjustment for performance status (P < 0.0001) and gender (P = 0.0041), the combination of HbL increase ≥2.3 g/dL and any grade hBP was significantly associated with longer PFS (HR = 0.40, 95%CI [0.24; 0.68]). CONCLUSIONS: Early HbL increase during axitinib treatment combined with hBP is an independent predictive factor of PFS. These results require validation in a prospective setting.

Utility of serum anti-cetuximab immunoglobulin E levels to identify patients at a high risk of severe hypersensitivity reaction to cetuximab.

AIM: Cetuximab is an anti-epidermal growth factor receptor antibody used for the treatment of metastatic colorectal cancer and head and neck cancer. Hypersensitivity reactions (HSRs) are associated with cetuximab use. The aim of the study was to evaluate the utility of anti-cetuximab immunoglobulin E (IgE) detection in order to identify patients at risk of HSR to cetuximab. METHODS: We included patients ready to receive a first cetuximab infusion in a prospective cohort carried out at nine French centres. Pretreatment anti-cetuximab IgE levels were measured. We compared the proportion of severe HSRs in the low anti-cetuximab IgE levels (≤29 IgE arbitrary units) subgroup with that in a historical cohort of 213 patients extracted from a previous study. RESULTS: Of the 301 assessable patients (mean age: 60.9 ± 9.3 years, head-and-neck cancer: 77%), 66 patients (22%) had high anti-cetuximab IgE levels, and 247 patients received cetuximab (including 38 with high anti-cetuximab levels). Severe HSRs occurred in eight patients (five grade 3 and three grade 4). The proportion of severe HSRs was lower in the low anti-cetuximab IgE levels subgroup vs. the historical cohort (3/209 [1.4%] vs. 11/213 [5.2%], odds ratio, 0.27, 95% confidence interval, 0.07-0.97), and higher in high vs. low anti-cetuximab IgE levels subgroup (5/38 [13.2%] vs. 3/209 [1.4%]; odds ratio, 10.4, 95% confidence interval, 2.4-45.6). Patients with severe HSRs had higher anti-cetuximab IgE levels than patients without reaction (median, 45 vs. 2 IgE arbitrary units, P = 0.006). CONCLUSIONS: Detection of pretreatment anti-cetuximab IgE is feasible and helpful to identify patients at risk of severe cetuximab-induced HSRs.

Retrospective evaluation of concomitant cetuximab and radiotherapy tolerance for locoregional advanced head and neck squamous cell carcinoma treatment in patients unfit for platinum-based chemotherapy.

Radiotherapy associated with cetuximab (Cet-RT) is an alternative treatment to platinum-based chemoradiotherapy in locally advanced head and neck carcinoma (LAHNC). Reviews suggest that the use of cetuximab is associated with poorer tolerance in patients unfit for chemotherapy than in pivotal trial. We retrospectively studied patients first treated by Cet-RT for LAHNC presenting contraindications to chemoradiotherapy. Objectives were treated population description, acute tolerance, progression-free survival (PFS), overall survival (OS), and 3-month clinical response. Eighty-eight patients were included. Treatment was completed without delay for 43 patients. Grade 3-4 acute toxicity was described in 44.3%: mucositis (n = 20), radiodermatitis (n = 25) folliculitis (n = 10), and anaphylaxis (n = 6). Fourteen patients died during treatment. Median PFS and OS were 6.3 and 18.7 months, respectively. We confirm that Cet-RT tolerance in unfit patients is poorer than that in trials. Survival data illustrate patients' frailty and suggest that balanced use of Cet-RT is required in this population.

How to improve the prevention of chemotherapy-induced nausea and vomiting? The French NAVI study.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) still remain frequent. The procedure for announcing the diagnosis (PAD) was an emblematic measure of the first French Plan Cancer aiming at providing patients with time to listen, information after cancer diagnosis, and discussion on treatments and their side effects. We aimed at assessing the risk factors of CINV, focusing on patients' satisfaction with the PAD. METHODS: This prospective multicentre study assessed the frequency and intensity of CINV among chemonaïve patients during the first cycle of treatment. CINV was defined by ≥1 emetic episode or reported nausea intensity ≥3 on a 0-10 scale. Multivariate analysis was used to identify factors related to global CINV onset including satisfaction with the PAD (satisfaction score ≥the median on a 0-10 scale). RESULTS: Data from 291 patients (women, 85.2%; mean age, 57 years) were analyzed. Most patients (69.4%) received highly emetogenic chemotherapy regimens and 77.7% received antiemetic drugs consistent with international guidelines. Acute, delayed and overall CINV were experienced by 40.4, 34.8 and 52.4% of patients, respectively. Sixty-seven per cent of patients were satisfied with the PAD. No relation was noted between PAD satisfaction and CINV onset. The nausea and vomiting dimension of the QLQ-C30 questionnaire before chemotherapy (OR 3.62), motion sickness history (OR 2.73), highly emetogenic CT (OR 2.73), anxiety (OR 1.99) and younger age (OR 1.96) were independent predictive factors. CONCLUSIONS: Although patients were mostly satisfied with the PAD, half of them experienced CINV. A state of anxiety could be identified during the PAD to be managed.

Identification of predictive factors of response to the BH3-mimetic molecule ABT-737: an ex vivo experiment in human serous ovarian carcinoma.

Ovarian cancers are addicted to Bcl-xL and Mcl-1, antiapoptotic members of the Bcl-2 family. Bcl-xL can be inhibited by the BH3-mimetic ABT-737. In vitro, ABT-737 can induce apoptosis of cancer cells, and its activity is potentiated by Mcl-1 inactivation. Herein, we assessed the sensitivity of human ovarian tumor nodes to ABT-737 when combined with carboplatin, which can indirectly inhibit Mcl-1. Fresh samples from 25 patients with high-grade serous ovarian cancer (HGSOC) who were chemo-naïve and had undergone surgery were prospectively exposed ex vivo to ABT-737 ± carboplatin. The treatment effect was studied on sliced tumor nodes by assessment of cleaved-caspase 3 immunostaining. We also studied the association between baseline Bcl-2 family protein expression (via immunohistochemistry) and the response of nodes to treatment. ABT-737 induced apoptosis as a single agent but its efficacy was not improved by the addition of carboplatin. Bim was frequently expressed (20/25) and its absence or low expression was associated with the absence of response to ABT-737, p value = 0.019 by Fisher's test and sensitivity = 93%, (95% confidence interval, 66-100). Moreover, we observed that in tumors in which Bim was expressed, a low expression of phospho-Erk1/2 or Mcl-1 improved the proportion of responses. This pilot study showed that ABT-737 has promise as monotherapy for HGSOC in a specific subgroup of tumors. Bim, Mcl-1, and phospho-Erk1/2 appeared to be relevant biomarkers that could be used for the selection of patients in the design of clinical trials using Navitoclax (an orally available compound related to ABT-737).

Staging the axilla in breast cancer patients with ¹8F-FDG PET: how small are the metastases that we can detect with new generation clinical PET systems?

PURPOSE: Point spread function (PSF) reconstruction improves spatial resolution throughout the entire field of view of a PET system and can detect smaller metastatic deposits than conventional algorithms such as OSEM. We assessed the impact of PSF reconstruction on quantitative values and diagnostic accuracy for axillary staging of breast cancer patients, compared with an OSEM reconstruction, with emphasis on the size of nodal metastases. METHODS: This was a prospective study in a single referral centre in which 50 patients underwent an (18)F-FDG PET examination before axillary lymph node dissection. PET data were reconstructed with an OSEM algorithm and PSF reconstruction, analysed blindly and validated by a pathologist who measured the largest nodal metastasis per axilla. This size was used to evaluate PET diagnostic performance. RESULTS: On pathology, 34 patients (68%) had nodal involvement. Overall, the median size of the largest nodal metastasis per axilla was 7 mm (range 0.5 - 40 mm). PSF reconstruction detected more involved nodes than OSEM reconstruction (p = 0.003). The mean PSF to OSEM SUVmax ratio was 1.66 (95 % CI 1.01 - 2.32). The sensitivities of PSF and OSEM reconstructions were, respectively, 96% and 92% in patients with a largest nodal metastasis of >7 mm, 60% and 40% in patients with a largest nodal metastasis of ≤7 mm, and 92% and 69% in patients with a primary tumour ≤30 mm. Biggerstaff graphical comparison showed that globally PSF reconstruction was superior to OSEM reconstruction. The median sizes of the largest nodal metastasis in patients with nodal involvement not detected by either PSF or OSEM reconstruction, detected by PSF but not by OSEM reconstruction and detected by both reconstructions were 3, 6 and 16 mm (p = 0.0064) respectively. In patients with nodal involvement detected by PSF reconstruction but not by OSEM reconstruction, the smallest detectable metastasis was 1.8 mm. CONCLUSION: As a result of better activity recovery, PET with PSF reconstruction performed better than PET with OSEM reconstruction in detecting nodal metastases ≤7 mm. However, its sensitivity is still insufficient for it to replace surgical approaches for axillary staging. PET with PSF reconstruction could be used to perform sentinel node biopsy more safely in patients with a primary tumour ≤30 mm and with unremarkable PET results in the axilla.

Scar extent as a predictive factor of ventricular tachycardia cycle length after myocardial infarction: implications for implantable cardioverter-defibrillator programming optimization.

AIMS: After an old myocardial infarction (MI), patients are at risk for reentrant ventricular tachycardia (VT) due to scar tissue that can be accurately identified by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Although the ability of LGE-CMR to predict sustained VT in implantable cardioverter-defibrillator (ICD) recipients has been well established, its use to predict monomorphic VT (sustained or not) cycle length (CL) and so, optimize ICD programming has never been investigated. METHODS AND RESULTS: We included retrospectively 49 consecutive patients with an old MI who had undergone LGE-CMR before ICD implantation over a 4-year period (2006-09). Patients with amiodarone used were excluded. Scar extent was assessed by measuring scar mass, percent scar, and transmural scar extent. The endpoint was the occurrence of monomorphic VT, requiring an ICD therapy or not. The endpoint occurred in 26 patients. The median follow-up duration was 31 months. Scar extent parameters were significantly correlated with the study endpoint. With univariate regression analysis, the scar mass had the highest correlation with the VT CL (R = 0.671, P = 0.0002). Receiver-operating characteristic curve showed that scar mass can predict VT CL (area under the curve = 0.977, P < 0.0001). For a cut-off value of scar mass at 17.6 g, there is 100% specificity and 94.4% sensitivity. CONCLUSION: In this observational and retrospective study, scar mass studied by LGE-CMR was specific and sensitive to predict VT CL and so could be a promising option to improve ICD post-implantation programming and decrease appropriate and inappropriate shocks. These conclusions must now be confirmed in a large and prospective study.

Rotational atherectomy for left main coronary artery disease in octogenarians: transradial approach in a tertiary center and literature review.

OBJECTIVES: The aim of this study was to appreciate the safety and effectiveness of transradial percutaneous coronary intervention (PCI) with rotational atherectomy for highly calcified left main coronary artery (LMCA) disease in octogenarians. BACKGROUND: Conventional surgery is still considered the preferred management for LMCA disease; but, when the lesion is severely calcified, and the patient is unsuitable for surgery, the interventional cardiologist faces a complex PCI traditionally approached by femoral access. METHODS: Between June 2004 and December 2010, octogenarians with calcified LMCA disease who were primary denied for surgical revascularization were enrolled. Procedural success and major adverse cerebral and cardiovascular events (MACCE) including death, nonfatal myocardial infarction, target lesion revascularization (TLR), or stroke during long-term follow-up were evaluated. RESULTS: Forty-two consecutive patients ≥80 years had undergone stenting for calcified LMCA disease (13 with rotational atherectomy, the "Rota" group, and 29 without rotational atherectomy, the "without Rota" group). Procedural success was good (92.3% vs. 96.6%, respectively, p = NS). Mean follow-up time was 25.7 ± 21.4 and 28 ± 32.3 months, respectively. There was a TLR in 25% and 11.1%, respectively; p = NS. No difference was detected in terms of overall in-hospital or long-term mortality or MACCE. CONCLUSION: Rotational atherectomy followed by stent implantation by transradial approach, when applied to heavily calcified lesions, appeared to be a safe and effective strategy for the treatment of LMCA disease in octogenarians who were refused for surgery.

Scar extent evaluated by late gadolinium enhancement CMR: a powerful predictor of long term appropriate ICD therapy in patients with coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) patients are at risk for life-threatening ventricular arrhythmias (VA) related to scar tissue. Late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) can accurately identify myocardial scar extent. It has been shown that scar extent, particularly scar transmurality, percent scar and scar mass, are associated with the occurrence of appropriate implantable cardioverter-defibrillator (ICD) therapy. However, quantification of transmurality extent has never been studied. The purpose of our study was to evaluate whether different methods quantifying scar transmurality, percent scar and scar mass (assessed with LGE-CMR) can predict appropriate ICD therapy in CAD patients with a long term follow-up period. METHODS AND RESULTS: We enrolled retrospectively 66 patients with chronic CAD referred for primary or secondary preventive ICD implantation and LGE-CMR before ICD implantation. Using LGE-CMR, scar extent was assessed by measuring scar mass, percent scar and transmural scar extent using four different methods. The median follow-up duration was 41.5 months (interquartile range 22-52). The endpoint was the occurrence of appropriate device therapy and occurred in 14 patients. Pre-ICD revascularization and transmural scar extent were significantly associated with the study endpoint but the latter was especially highly dependent on the method used. Patients with appropriate device therapy had also larger scar mass (29.6 ± 14.5 g vs 17.1 ± 8.8 g, p = 0.004), and larger percent scar (15.1 ± 8.2% vs 9.9 ± 5.6%, p = 0.03) than patients without appropriate device therapy. In multivariate analysis, scar extent variables remained significantly associated with the study end-point. CONCLUSIONS: In this study of CAD patients implanted for primary or secondary preventive ICD, pre-ICD revascularization and scar extent studied by LGE-CMR were significantly associated with appropriate device therapy and can identify a subgroup of CAD patients with an increased risk of life-threatening VA. Depending of the method used, transmural scar extent may vary significantly and needs further studies to obtain a validated and consensual study method.

Sunglasses with thick temples and frame constrict temporal visual field.

PURPOSE: Our aim was to compare the impact of two types of sunglasses on visual field and glare: one ("thick sunglasses") with a thick plastic frame and wide temples and one ("thin sunglasses") with a thin metal frame and thin temples. METHODS: Using the Goldmann perimeter, visual field surface areas (cm²) were calculated as projections on a 30-cm virtual cupola. A V4 test object was used, from seen to unseen, in 15 healthy volunteers in the primary position of gaze ("base visual field"), then allowing eye motion ("eye motion visual field") without glasses, then with "thin sunglasses," followed by "thick sunglasses." Visual field surface area differences greater than the 14% reproducibility error of the method and having a p < 0.05 were considered significant. A glare test was done using a surgical lighting system pointed at the eye(s) at different incidence angles. RESULTS: No significant "base visual field" or "eye motion visual field" surface area variations were noted when comparing tests done without glasses and with the "thin sunglasses." In contrast, a 22% "eye motion visual field" surface area decrease (p < 0.001) was noted when comparing tests done without glasses and with "thick sunglasses." This decrease was most severe in the temporal quadrant (-33%; p < 0.001). All subjects reported less lateral glare with the "thick sunglasses" than with the "thin sunglasses" (p < 0.001). CONCLUSIONS: The better protection from lateral glare offered by "thick sunglasses" is offset by the much poorer ability to use lateral space exploration; this results in a loss of most, if not all, of the additional visual field gained through eye motion.

Predictive factors for lateral occult lymph node metastasis in papillary thyroid carcinoma.

Management of lateral no necks in papillary thyroid carcinoma (PTC) is very controversial. The aim of this study was to find predictive factors of lateral neck involvement in N0 PTC to help the clinician in his decision to treat the lateral compartment. We retrospectively analysed 173 patients who underwent thyroidectomy and lateral prophylactic neck dissection for PTC >10 mm. Predictive factors for occult lateral lymph node metastasis including sex, age, tumour size, multifocality and bilaterality, tumour extracapsular spread, vascular invasion and presence of a tumour capsule were examined by multivariate analysis. There were three independent predictive factors for occult lateral lymph node metastases in multivariate analysis: tumour extracapsular spread (p < 0.0001), vascular invasion (p < 0.001) and age <45 years (p < 0.027). When none of these factors was present, the risk of occult metastases was <5 %. The risk increased up to 56 % when at least two of these factors were present. These findings suggest that, in patients older than 45 years with neither tumour extracapsular spread nor vascular invasion on histopathological examination, occult lymph node metastases are very uncommon. In that case further discussion regarding the risks and benefits of lateral nodal dissection may be warranted.

O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation and low MGMT-encoded protein expression as prognostic markers in glioblastoma patients treated with biodegradable carmustine wafer implants after initial surgery followed by radiotherapy with concomitant and adjuvant temozolomide.

BACKGROUND: O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation status was proposed as a prognostic biomarker for patients with glioblastoma. However, the prognostic impact of MGMT in patients with newly diagnosed glioblastoma who receive carmustine-releasing wafers (Gliadel) along with temozolomide (TMZ) is still unknown. METHODS: MGMT promoter methylation status and protein expression were analyzed in formalin-fixed, paraffin-embedded tumor specimens obtained from 111 French patients with newly diagnosed glioblastoma. Patients received the Gliadel wafers followed by radiotherapy plus concomitant and adjuvant TMZ chemotherapy while they were enrolled in a French multicenter prospective study. RESULTS: For the whole cohort, the median overall survival (OS) was 17.5 months, and the progression-free survival was 10.3 months. Patients with tumors that harbored MGMT methylation had a significantly longer OS compared with patients who had wild-type MGMT (21.7 months vs 15.1 months; P = .025). Similarly, patients who had low MGMT protein expression (≤15%) had a significantly improved OS compared with patients who had high MGMT expression (27.0 months vs 15.1 months; P = .021). The extent of resection was the strongest clinical predictor of outcome. In multivariate Cox models that were adjusted for sex, performance status, and extent of surgery, both MGMT methylation and protein expression were identified as independent prognosticators, and the finding was validated internally using a bootstrap resampling technique. Discrepancies were identified between protein expression and MGMT methylation status, thus suggesting that the 2 assays probably assess different biologic features. CONCLUSIONS: MGMT promoter methylation status and low MGMT expression both were identified as positive prognosticators in patients with newly diagnosed glioblastoma who underwent surgical resection and received Gliadel wafer implants followed by adjuvant radiotherapy and concomitant oral TMZ chemotherapy (the Stupp protocol).

Long-term results of 81 prevertebral subclavian artery angioplasties: a 26-year experience.

BACKGROUND: Long-term results of transluminal angioplasty (TLA) of the prevertebral subclavian artery (PVSA) are not well known. The aim of this work was to present a retrospective analysis of a consecutive series of 81 TLAs of the PVSA, with a mean follow-up of approximately 7 years (82 months). MATERIAL AND METHODS: From January 1984 to May 2007, 81 TLAs of PVSA were consecutively performed in 72 patients (64% men; median age = 56.7 years) to treat 71 tight stenoses and 10 occlusions. In 58 cases, TLA was carried out under local anesthesia (71.6%), 65 times by femoral approach, and 16 times by humeral approach. A percutaneous approach was used 72 times (89%). A stent was placed in 18 cases (22.2%). RESULTS: Immediate technical success rate was 93%. One transient monoplegia was noticed after TLA and four puncture complications were observed, which occurred significantly more frequently with percutaneous humeral approach (p = 0.024). A recurrent stenosis occurred 28 times (34.6%) and was symptomatic in three cases. With a mean 82-month follow-up (3-299 months), primary patency at 10 years was 85.2% and primary assisted patency was 92.6%. No restenosis occurred after the 25th month of the follow-up. No restenosis factor was statistically predictive. CONCLUSION: TLA of the PVSA is a mildly invasive and efficient treatment. Early restenoses are frequent but remain accessible to a new TLA with stable long-term results.

BRCA1 allele-specific expression in genetic predisposed breast/ovarian cancer.

Germline allele specific expression (ASE), resulting in a lowered expression of one of the BRCA1 alleles, has been described as a possible predisposition marker in Hereditary Breast or Ovarian Cancer (HBOC), usable for molecular diagnosis in HBOC. The main objective of this prospective case-control study was to compare the proportion of ASE between controls without familial history of breast or ovarian cancer, and HBOC cases without BRCA1 or BRCA2 deleterious mutation. BRCA1 ASE evaluated on three SNPs among controls and HBOC patients without deleterious mutation were assessed by pyrosequencing. The allelic ratios and the proportion of ASE were compared between controls and cases using a Student's t test and a Fisher exact test, respectively. The linearity and reproducibility of the ASE dosage was demonstrated with R2 > 0.99 and a coefficient of variation below 10 %, and ASE was detected in two positive controls harbouring BRCA1 truncated mutations. In the heterozygote population, composed of 99/264 controls (37.5 %) and 96/227 patients (42.3 %), we detected a 5 % ASE without truncated mutations, in each population. We failed to detect any significant difference of ASE between controls and patients. So far, BRCA1 Allelic specific expression is not usable in routine diagnosis as a possible predisposition marker in HBOC patients except for the detection of truncated mutations.

How to Deal with Interval-Censored Data Practically while Assessing the Progression-Free Survival: A Step-by-Step Guide Using SAS and R Software.

We describe how to estimate progression-free survival while dealing with interval-censored data in the setting of clinical trials in oncology. Three procedures with SAS and R statistical software are described: one allowing for a nonparametric maximum likelihood estimation of the survival curve using the EM-ICM (Expectation and Maximization-Iterative Convex Minorant) algorithm as described by Wellner and Zhan in 1997; a sensitivity analysis procedure in which the progression time is assigned (i) at the midpoint, (ii) at the upper limit (reflecting the standard analysis when the progression time is assigned at the first radiologic exam showing progressive disease), or (iii) at the lower limit of the censoring interval; and finally, two multiple imputations are described considering a uniform or the nonparametric maximum likelihood estimation (NPMLE) distribution. Clin Cancer Res; 22(23); 5629-35. ©2016 AACR.

Pairwise comparison of 18F-FDG and 18F-FCH PET/CT in prostate cancer patients with rising PSA and known or suspected second malignancy.

OBJECTIVE: This study aimed to evaluate the usefulness of combining fluorine-18 choline (F-FCH) and fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in patients with rising prostate-specific antigen and known or suspected second malignancy. MATERIALS AND METHODS: F-FCH and F-FDG PET/CT were performed 15±9 days apart on the same PET/CT system and acquisition and reconstruction parameters. A mean standardized uptake value (SUVmean) was computed for every lesion that could be discriminated with both tracers. PET results were confirmed by histology (eight patients) and clinical and imaging follow-up (mean±SD: 15±9 months). RESULTS: Of 77 consecutive patients who underwent F-FCH PET/CT scans for suspected prostate cancer recurrence, 10 (13%) were suspected to have a second malignancy because of F-FCH PET pattern inconsistency with that of prostate cancer (n=6), because of a history of a second malignancy with similar metastatic patterns (n=2) or inconsistency between disease burden and prostate-specific antigen value (n=2). Seventy lesions were studied, with a final diagnosis of prostate cancer, other cancers and benign disease in 55, nine and six lesions, respectively. F-FCH SUVmean and F-FCH/F-FDG SUVmean ratios were significantly different between prostate cancer, nonprostate cancer and benign disease (P<0.0001 and P=0.04, respectively). Receiving operating characteristic analysis showed that the F-FCH/F-FDG ratios were not better than F-FCH SUVmean in discriminating prostate cancer from nonprostate cancer and benign diseases (sensitivity, specificity and area under the curve were 69%, 80%, 0.71 and 84%, 80% and 0.89, respectively). CONCLUSION: We found that F-FCH/F-FDG SUVmean ratios cannot differentiate prostate cancer recurrences from other cancer types when both diagnoses are suspected. Doubtful lesions should be biopsied.

Predictive factors of 18F-choline PET/CT positivity in patients with prostate cancer recurrence after radiation therapy: is the impact of PSA nadir underestimated?

BACKGROUND: The objective of this study is to explore the impact of PSA nadirs on detection rates of prostate cancer (PCa) recurrence with 18F-choline (CH) PET/CT after external beam radiation therapy (EBRT). METHODS: In this retrospective study, data were collected from 54 patients with suspicion of PCa biochemical recurrence after EBRT (28 patients treated initially with EBRT and 26 as salvage therapy in the absence of PSA decrease after initial treatment), who underwent 18F-CH PET/CT between 2010 and 2015. PSA nadir and trigger PSA were collected from patient files. Relative PSA was calculated by subtracting the nadir from the trigger PSA. RESULTS: Median PSA nadir was 0.31 (0.01-13.31) ng/mL, trigger PSA was 7.85 (0.47-111.60) ng/mL, and relative PSA was 6.05 (0.24-104.59) ng/mL. Overall, 40 (74%) PET/CT scans were positive: recurrence was local and/or regional in 29 patients, distant in 15 and combined both in four, with no association between PSA values and sites of recurrence. In univariate analysis, trigger (p = 0.015) and relative (p = 0.0005) PSA values and PSA velocity (p = 0.01) were significantly linked to positive PET/CT, but PSA nadir was not. In subgroup analysis, these significant differences were only found in the salvage EBRT group. Akaike Information Criterion multivariate model comparison found that relative PSA was a better predictor of positive PET/CT than trigger PSA (PSAt). 18F-CH PET/CT detection rates increased with trigger and relative PSA: 0% (0/4 patients), 71% (5/7 patients), and 81% (35/43 patients) for PSAt <2 ng/mL, 2≤ PSAt ≤4 ng/mL, and PSAt >4 ng/mL, respectively, and 14% (1/7 patients), 50% (5/10 patients), and 92% (34/37 patients) when relative PSA was taken into account instead of trigger PSA, with seven (13%) patients changing subgroups. CONCLUSIONS: We found a high overall detection rate and an increase in detection rates proportional to trigger and relative PSAs. Although relative PSA, taking into account PSA nadir, was a better predictive factor of PET/CT positivity in univariate analysis, this was most noticeable for high PSAs. For low PSAs, trigger PSA remains most relevant. Larger series with intermediate PSA values need to be studied to fully apprehend nadir impact.