scholarly journals Macdonald criteria for glioblastoma

2014 ◽  
Author(s):  
Frank Gaillard
Keyword(s):  
Macdonald Criteria

Short Course Radiotherapy Concomitant with Temozolomide in GBM Patients: A Phase II Study

2017 ◽  
Vol 103 (5) ◽  
pp. 457-463 ◽  
Author(s):  
Laura Fariselli ◽  
Lucia Cuppini ◽  
Paola Gaviani ◽  
Marcello Marchetti ◽  
Valentina Pinzi ◽  
...  
Keyword(s):  
Total Dose ◽  
Phase Ii ◽  
Local Control ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Treatment Schedule ◽  
Open Label ◽  
Macdonald Criteria ◽  
Secondary Endpoints ◽  
Group B

Purpose Despite recent advances, the prognosis of glioblastoma (GBM) remains poor. The aim of this study was to assess the efficacy and tolerability of multiple daily fraction radiotherapy performed with multiple temozolomide (TMZ) administrations in newly diagnosed patients with GBM. Methods This trial was a prospective, open-label, monocentric, nonrandomized, single arm, phase II study. The primary endpoint was the proportion of progression-free patients at 12 months, and the secondary endpoints were overall survival (OS) and toxicity. Thirty-five patients underwent two radiotherapy courses concomitant with TMZ after surgery. At each course, radiation was delivered 3 times daily, 2 Gy/fraction, for 5 consecutive days, and the total dose was 60 Gy; concurrent TMZ was administered in a total dose of 150-200 mg/m2/day. Results The primary endpoint failed to be applied; Macdonald criteria could be used in 16 (46%) patients with local or intracerebral recurrence (group A). In 12 patients, due to suspicion of radiation necrosis vs recurrence, Macdonald criteria were not applied (group B). The OS was 22 months, and OS probabilities at 12, 18, and 24 months were 82%, 59%, and 44%, respectively. Hematologic toxicities generally did not exceed grade 2. The quality of life and cognitive functioning did not significantly change between baseline and the first follow-up. In the multivariate analysis, necrosis and pseudoprogression were significant prognostic factors of OS. Conclusions To improve local control and OS, a more aggressive treatment schedule should be explored. The related higher necrosis risk and its implications regarding local control deserve further investigation.

Imaging Criteria in Neuro-oncology

2018 ◽  
Vol 38 (01) ◽  
pp. 024-031 ◽  
Author(s):  
Martha Nowosielski ◽  
Patrick Wen
Keyword(s):  
Clinical Trials ◽  
Brain Tumors ◽  
Imaging Techniques ◽  
Response Assessment ◽  
Pediatric Brain Tumors ◽  
Macdonald Criteria ◽  
Collective Work ◽  
Positron Emission ◽  
Oncology Clinical Trials ◽  
Group A

The identification of more effective therapies for brain tumors has been limited in part by the lack of reliable criteria for determining response and progression. Since its introduction in 1990, the MacDonald criteria have been used in neuro-oncology clinical trials to determine response, but they fail to address issues such as pseudoprogression, pseudoresponse, and nonenhancing tumor progression that have arisen with more recent therapies. The Response Assessment in Neuro-Oncology (RANO) working group, a multidisciplinary international group consisting of neuro-oncologists, medical oncologists, neuroradiologists, neurosurgeons, radiation oncologists, and neuropsychologists, was formed to improve response assessment and clinical trial endpoints in neuro-oncology. Although it was initially focused on response assessment for gliomas, the scope of the RANO group has been broadened to include brain metastases, leptomeningeal metastases, spine tumors, pediatric brain tumors, and meningiomas. In addition, subgroups have focused on response assessment during immunotherapy and use of positron emission tomography, as well as determination of neurologic function, clinical outcomes assessment, and seizures. The RANO criteria are currently a collective work in progress, and refinements will be needed in the future based on data from clinical trials and improved imaging techniques.

Treatment of gliomatosis cerebri with temozolomide: A retrospective study of the AINO (Italian Association for Neuro- Oncology)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2033-2033 ◽  
Author(s):  
R. Soffietti ◽  
R. Rudà ◽  
E. Laguzzi ◽  
L. Buttolo ◽  
A. Pace ◽  
...  
Keyword(s):  
Response Rate ◽  
Haematological Toxicity ◽  
Gliomatosis Cerebri ◽  
Large Field ◽  
Minor Response ◽  
Neurological Improvement ◽  
Macdonald Criteria ◽  
Pre Treatment ◽  
Dose Dense ◽  
A Minor

2033 Background: The optimal management for patients with primary gliomatosis cerebri is unknown, and some recent studies suggest that temozolomide could be useful as an upfront treatment. Methods: Between 1999 and 2005, 46 patients with biopsy proven gliomatosis cerebri were treated with temozolomide either upfront or at progression after prior radiotherapy/chemotherapy. Histological diagnoses were as follows: glioblastoma in 3 patients, malignant glioma in 8, anaplastic astrocytoma in 8, gemistocytic astrocytoma in 2, astrocytoma in 13, anaplastic oligodendroglioma in 1, anaplastic oligoastrocytoma in 1, oligoastrocytoma in 1, oligodendroglioma in 4, glial proliferation consistent with GC in 5. Median age was 49 years (range 14–70), with 20 males and 26 females and a median KPS at diagnosis of 80 (range 50–90). Twenty-three out of 46 (50%) pre-treatment MRI demonstrated some degree of contrast enhancement. Twenty-three of 46 patients were treated upfront, while 23 had received prior radiation therapy or nitrosourea-based chemotherapy. All patients received temozolomide 200 mg/m2 die for 5 days every 4 weeks until progression or unacceptable toxicity. Response was evaluated, according to Macdonald criteria, on T1-weighted with Gadolinium and FLAIR images. Results: Two patients (4%) showed a CR of the contrast enhancing area, 2 patients (4%) a PR, 5 (11%) a minor response, 18 (39%) a SD and 19 (42%) a PD. Overall response rate (CR + PR + “minor response”) was 19%, while a clinical benefit was observed in 13/46 patients (28%). Median TTP was 9 months (range 1–27), and median survival 14 months (range 3–123). PFS at 6 months was 57%, at 12 months 35%. Oligodendroglial tumours showed a 38% response rate and a TTP of 11 months. Response rate was higher among patients treated at progression compared to those treated upfront (13% versus 26%). Grade III-IV haematological toxicity was mild. Conclusions: Temozolomide has some activity in primary GC (19% response rate), and is well tolerated. A significant neurological improvement can be observed in patients with either response or stable disease on MRI. To improve the efficacy of temozolomide in the upfront setting (in order to delay a large field RT), a phase II study with a dose-dense regimen is ongoing. No significant financial relationships to disclose.

Pazopanib and lapatinib in patients with relapsed malignant glioma: Results of a phase I/II study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2040-2040
Author(s):  
S. N. Frentzas ◽  
M. D. Groves ◽  
J. Barriuso ◽  
D. Harris ◽  
D. Reardon ◽  
...  
Keyword(s):  
Phase I ◽  
Malignant Glioma ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Angiogenesis Inhibitor ◽  
Macdonald Criteria ◽  
Best Response ◽  
Elevated Liver Enzymes ◽  
Adequate Organ Function ◽  
Grade 3

2040 Background: Pazopanib (paz) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit; and lapatinib (lap) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER-2 (ErbB2). Combination of VEGFR, PDGFR, and ErbB1 inhibitors may provide synergistic antitumor activity in malignant glioma. Phase I determined the optimally tolerated regimen (OTR) of paz and lap when given with enzyme-inducing anticonvulsants (EIACs). Phase II, which evaluated the efficacy of daily paz/lap (400 mg/1000mg) in relapsed grade 4 glioma without EIACs, was previously reported. Methods: Patients (pts) with grade 3 or 4 glioma, on EIACs, and with adequate organ function were eligible. Doses of paz and lap were escalated in a 3 + 3 design. OTR was defined as the highest dose of paz/lap at which no more than 1 of 6 pts had dose limiting toxicity (DLT) and target concentrations were achieved. Results: 32 pts have been enrolled at doses of paz/lap (mg, daily unless specified) of 200/1500 (N = 4), 800/1500 (N = 6), 800/500 bid (N = 5), 800/750 bid (N = 7), 800/1000 bid (N = 6), and 600 bid/1000 bid (N = 4). Data on 28 pts: the most common adverse events (AEs) were: fatigue (25%); diarrhea (25%); headache (21%); ALT increase (18%); nausea (18%); and insomnia (14%). Hepatobiliary lab abnormalities were reversible, uncomplicated, and included: AST elevation (11%), hyperbilirubinemia (7%), ALT elevation (36%; 7% Gr 3), and Alk phos elevation (14%). DLTs were elevated liver enzymes (800/1500; 1 pt), elevated lipase (800/750 bid; 1 pt) and thrombocytopenia, fatigue, diarrhea, confusion (800/1000 bid; 1 pt). 2 pts dose reduced and 3 pts had a dose interruption. At 600 bid/1000 bid, the target paz Cmin of 17.5 μg/mL was achieved; median lap Cmin of 0.447 μg/mL approached the target of 0.5 μg/mL. Phase I best response (MacDonald criteria) was PR in 3 pts (11%) and SD ≥ 8 weeks in 5 pts (18%). Two pts remain on the phase II, at 21 months (PR) and 23 months (CR) of therapy. Conclusions: The paz/lap combination has a manageable safety profile with a preliminary OTR with EIACs of paz 600 mg bid/ lap 1000 mg bid. EIACs decreased plasma paz and lap concentrations. Responses and lengthy periods without disease progression were seen in some pts in phase I and II. [Table: see text]

scholarly journals A novel, reproducible, and objective method for volumetric magnetic resonance imaging assessment of enhancing glioblastoma

2014 ◽  
Vol 121 (3) ◽  
pp. 536-542 ◽  
Author(s):  
Charles W. Kanaly ◽  
Ankit I. Mehta ◽  
Dale Ding ◽  
Jenny K. Hoang ◽  
Peter G. Kranz ◽  
...  
Keyword(s):  
Interobserver Variability ◽  
Intraclass Correlation ◽  
Evaluation Criteria ◽  
Correlation Coefficients ◽  
Response Assessment ◽  
Volumetric Method ◽  
Kappa Statistics ◽  
Macdonald Criteria ◽  
Automated Method ◽  
Radiological Response

Object Robust methodology that allows objective, automated, and observer-independent measurements of brain tumor volume, especially after resection, is lacking. Thus, determination of tumor response and progression in neurooncology is unreliable. The objective of this study was to determine if a semi-automated volumetric method for quantifying enhancing tissue would perform with high reproducibility and low interobserver variability. Methods Fifty-seven MR images from 13 patients with glioblastoma were assessed using our method, by 2 neuroradiologists, 1 neurosurgeon, 1 neurosurgical resident, 1 nurse practitioner, and 1 medical student. The 2 neuroradiologists also performed traditional 1-dimensional (1D) and 2-dimensional (2D) measurements. Intraclass correlation coefficients (ICCs) assessed interobserver variability between measurements. Radiological response was determined using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines and Macdonald criteria. Kappa statistics described interobserver variability of volumetric radiological response determinations. Results There was strong agreement for 1D (RECIST) and 2D (Macdonald) measurements between neuroradiologists (ICC = 0.42 and 0.61, respectively), but the agreement using the authors' novel automated approach was significantly stronger (ICC = 0.97). The volumetric method had the strongest agreement with regard to radiological response (κ = 0.96) when compared with 2D (κ = 0.54) or 1D (κ = 0.46) methods. Despite diverse levels of experience of the users of the volumetric method, measurements using the volumetric program remained remarkably consistent in all users (0.94). Conclusions Interobserver variability using this new semi-automated method is less than the variability with traditional methods of tumor measurement. This new method is objective, quick, and highly reproducible among operators with varying levels of expertise. This approach should be further evaluated as a potential standard for response assessment based on contrast enhancement in brain tumors.

Bevacizumab, a monoclonal antibody to the vascular endothelial growth factor (VEGF), and irinotecan for treatment of recurrent primary malignant brain tumors in adults

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 12503-12503 ◽  
Author(s):  
U. Lassen ◽  
K. Grunnet ◽  
M. Kosteljanetz ◽  
B. Hasselbalch ◽  
H. Laursen ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Tumor Regression ◽  
Malignant Gliomas ◽  
Complete Response ◽  
Consecutive Series ◽  
Topoisomerase 1 ◽  
Malignant Brain Tumors ◽  
Macdonald Criteria ◽  
Number Of Patients ◽  
Tumor Reduction

12503 Background: The prognosis of recurrent malignant brain tumors is poor, and no efficacious therapy exists in patients previously treated with radiotherapy and standard chemotherapy. Bevacizumab (B) binds to VEGF and inhibits tumor angiogenesis, and treatment with this drug might induce tumor regression and prolongation of life. Irinotecan (I) is a topoisomerase 1 inhibitor with modest effect on recurrent primary brain tumors. The combination of B and I in recurrent malignant gliomas was presented at ASCO 2006 and showed very encouraging responses. Methods: We report confirmatory results of the combination of B and I in a consecutive series of patients with primary malignant brain tumors recurring after standard primary and secondary treatment (surgery, radiotherapy and standard or secondline chemotherapy).With standard inclusion criteria, including PS 0–2, patients received B as 10mg/kg, and I 125 mg/m2 in patients not treated with enzyme inducing antiepileptic drugs (EIAED) or 340 mg/m2 in patients treated with EIAED every other week until progression or non-manageable toxicity. Response evaluation was performed by MacDonald criteria and MRI scans. Results: The results of 31 patients is presented, 15 with grade IV tumors (Glioblastoma multiforme), 7 with grade III anaplastic astrocytomas, 5 with anaplastic oligodendrogliomas, 1 with anaplastic ependymoma, 1 with hemangiopericytoma, 1 with prolactinoma, and 1 with medulloblastoma. Four patients had complete response, 3 grade IV tumors and 1 anaplastic oligodendroglioma. One patient had partial response (> 50% tumor reduction), 12 had stable disease (3 had tumor reduction between 31 - 45 %). 14 progressed. No grade 4 toxicity was observed and most patients experienced grade 1–2 toxicity. Two tromboembolic events and 1 intestinal perforation were observed. Conclusion: The combination of B and I is safe, induces tumor regression in a substantial number of patients, and can be used as treatment to patients recurring after standard treatment. No significant financial relationships to disclose.

Bevacizumab in combination with temozolomide in the adjuvant treatment of newly diagnosed glioblastoma multiforme: Preliminary results of a phase II study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2016-2016
Author(s):  
M. K. Nicholas ◽  
R. V. Lucas ◽  
J. Arzbaecher ◽  
N. Paleologos ◽  
H. Krouwer ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Disease Progression ◽  
Primary Brain Tumor ◽  
Newly Diagnosed ◽  
Duration Of Treatment ◽  
Current Standard ◽  
Fractionated Radiotherapy ◽  
Macdonald Criteria ◽  
Tolerability Data ◽  
Gi Bleed

2016 Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Current standard treatment consists of fractionated radiotherapy (RT) with daily oral temozolomide (TMZ) chemotherapy followed by 6 months of adjuvant TMZ chemotherapy. Median survival is 14.3 months. Because GBM is characterized by vascular proliferation and produces high levels of vascular endothelial growth factor (VEGF), attempts to better control the disease with targeted anti-angiogenesis therapies are underway. Here, we report preliminary safety and tolerability data of bevacizumab (BV) when added to monthly TMZ chemotherapy. Methods: Subjects received standard regional RT to a dose of 60 Gy in 30 fractions with dailyconcurrent TMZ (75 mg/m2) within 3–5 weeks of diagnosis. Four weeks after RT/TMZ, subjects received 5 consecutive daily TMZ doses (150–200 mg/m2) administered every 28 days. BV (10mg/kg) was given every 14 days. Treatment continued until either disease progression or unacceptable toxicity occurred. Results: 42 of 48 planned subjects were enrolled as of 12/30/08. Twenty-three remained on study. Of these, 4 were receiving RT/TMZ, 18 were receiving TMZ/BV and 1 was delayed post-RT/TMZ due to local wound infection. Nineteen were off-study. Eleven of those off-study never received BV due to: study withdrawal (n = 2), toxicity during RT/TMZ (n = 3) and post-RT/TMZ progression (n = 6). Seven subjects progressed while receiving TMZ/BV. Twenty-six of the 42 enrolled received at least one 28-day cycle of TMZ/BV (range 1 - 16 cycles). Duration of treatment, inclusive of RT/TMZ, ranged from 27 to 523 days. Best radiographic responses of evaluable subjects, using MacDonald criteria were: 5 complete, 9 partial, 13 stable and 7 progressive disease. Of those taken off study, 13 were due to disease progression. Of those removed from study due to toxicity, none were unexpected and only 1 (a GI bleed) occurred during the TMZ/BV phase. A statistical analysis of response and survival is pending. Conclusions: The co-administration of TMZ/BV following RT/TMZ for newly diagnosed GBM is safe and well-tolerated. [Table: see text]

Addition of continuous low dose temozolomide (T) to bevacizumab (Bev) plus irinotecan (Iri) after bevacizumab plus irinotecan failure in heavily pretreated glioblastoma multiforme (GBM)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13015-e13015
Author(s):  
S. Stankewitz ◽  
G. Dresemann
Keyword(s):  
Median Duration ◽  
Low Dose ◽  
Performance Status ◽  
Objective Response ◽  
Ecog Performance Status ◽  
Chemotherapeutic Regimen ◽  
Macdonald Criteria ◽  
Phase Ii Studies ◽  
Mri Scans ◽  
Grade 3

e13015 Background: In several phase II studies in relapsed GBM, Bev plus Iri showed impressive objective response rates (>50%) with acceptable toxicity rate, duration of response, however, was moderate. Methods: From April 2007 to October 2008, 35 pretreated patients with confirmed GBM with progressive disease (PD) after Bev (4 mg/kg body weight i.v.) plus Iri (80 mg/m2 i.v.) were treated with additional continuous low dose T (20 mg per day p.o.) while Bev plus Iri were continued. ECOG performance status (PF) was 0 - 2 in all pts. MRI scan was required after 4 weeks and every 6 weeks afterwards. MacDonald criteria were used for evaluation of response. If MRI scans could not be performed, patients were considered to have PD. Treatment was given until PD or intolerable toxicity occurred. Results: All 35 patients were eligible for toxicity and efficacy, median follow up was 7 months (2 - 20), 25 patients were male, 10 female, median age was 51 years (29 - 80), 21 patients had primary GBM, 14 patients secondary GBM. All patients had prior irradiation (56 - 60 Gy) 2 patients had 5, 8 patients had 4, 15 patients had 3, and 10 patients 2 prior chemotherapeutic regimen. 1 patient developed grade 3 leucopenia, and 1 patients grade 3 thrombopenia; 3 patients asymptomatic intracerebral bleeds requiring treatment delay, 1 pat. grade 3 sepsis and 2 patients grade 3 fatigue. In 4/35 patients a partial response (PR) was achieved, in 14/35 patients a disease stabilization for at least 2 months, while 17/35 patients showed primary PD. Median duration of PR was 3.5 months (2–5), median duration of SD was 5 months (2–13), Median survival was 5 months (2–13). Data will be updated. Conclusions: The addition of continuous low dose T in combination with Bev plus Iri seems to have activity in GBM patients, after progression on Bev plus Iri treatment, and has an acceptable toxicity profile. Further investigation of the combination Bev plus Iri plus T in GBM patients is necessary. No significant financial relationships to disclose.

scholarly journals Early Pseudoprogression following Chemoradiotherapy in Glioblastoma Patients: The Value of RANO Evaluation

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Paulo Linhares ◽  
Bruno Carvalho ◽  
Rita Figueiredo ◽  
Rui M. Reis ◽  
Rui Vaz
Keyword(s):  
Survival Data ◽  
Response Assessment ◽  
Rank Analysis ◽  
Rano Criteria ◽  
Macdonald Criteria ◽  
Kaplan Meier ◽  
Early Progression ◽  
Radiological Response ◽  
The Impact ◽  
True Progression

Introduction. The aim of this study was to determine the frequency of pseudoprogression in a cohort of glioblastoma (GBM) patients following radiotherapy/temozolomide (RT/TMZ) by comparing Macdonald criterial to Response Assessment in Neuro-Oncology (RANO) criteria. The impact on prognosis and survival analysis was also studied.Materials and Methods. All patients receiving RT/TMZ for newly diagnosed GBM from January 2005 to December 2009 were retrospectively evaluated, and demographic, clinical, radiographic, treatment, and survival data were reviewed. Updated RANO criteria were used for the evaluation of the pre-RT and post-RT MRI and compared to classic Macdonald criteria. Survival data was evaluated using the Kaplan-Meier and log-rank analysis.Results and Discussion. 70 patients were available for full radiological response assessment. Early progression was confirmed in 42 patients (60%) according to Macdonald criteria and 15 patients (21%) according to RANO criteria. Pseudoprogression was identified in 10 (23.8%) or 2 (13.3%) patients in Macdonald and RANO groups, respectively. Cumulative survival of pseudoprogression group was higher than that of true progression group and not statistically different from the non-progressive disease group.Conclusion. In this cohort, the frequency of pseudoprogression varied between 13% and 24%, being overdiagnosed by older Macdonald criteria, which emphasizes the importance of RANO criteria and new radiological biomarkers for correct response evaluation.

Re-challenge with temozolomide (TMZ) at recurrence in high-grade gliomas (HGG)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2034-2034 ◽  
Author(s):  
T. Jauch ◽  
P. Hau ◽  
U. Bogdahn
Keyword(s):  
Progressive Disease ◽  
Progression Free Survival ◽  
Time To Progression ◽  
Front Line ◽  
Prospective Data ◽  
Free Survival ◽  
Patient Request ◽  
Macdonald Criteria ◽  
A Prospective Study ◽  
Alternative Regimen

2034 Background: TMZ is standard therapy for patients (pts) with HGG. Recent data suggest potentially enhanced efficacy of alternative schedules of TMZ administration based on optimizing depletion of MGMT. However, no prospective data have been published on the efficacy of TMZ regimens after failure of first-line TMZ (FL-TMZ). We therefore assessed the outcome of rechallenge with TMZ in pts with HGG. Methods: A retrospective review of pt with recurrent HGG who were rechallenged with TMZ between Jan 2000 and Oct 2006 was conducted. Standard criteria for rechallenge were as follows: if pts relapsed=8 wks after discontinuation of FL-TMZ, they were treated with the same or an alternative regimen of TMZ; however, if they progressed while still receiving TMZ, they were treated with an alternative regimen. Results: Of a total 81 pts identified, 54 intra-institutional pts were evaluable, 23 glioblastoma (GBM), 22 anaplastic glioma (AG). Median age was 44 yr with median KPS of 80. The response rate (RR) to FL-TMZ was 65% in GBM and 95% in AG using Macdonald criteria. At rechallenge, pts received one of four TMZ regimens: 150–200 mg/m2/d for 5/28 days (n=35), 150 mg/m2/d for 7/14 days (n=7), 75 mg/m2/d for 21/28 days (n=4), or continuous 50 mg/m2/d (n=7). All pts had progressed during FL-TMZ or after initial discontinuation of TMZ. Discontinuation during rechallenge TMZ was due to progressive disease in 36 pts and patient request in 6 pts. None of the pts discontinued due to toxicity. The response rates were 66% and 70% in GBM and AG, respectively. 8/12 non-responders to FL-TMZ responded to alternate regimens of TMZ. Median time to progression (TTP) was 20 weeks and 22 weeks, respectively. Six-month progression-free survival was 41% in GBM and 43% in AG. Conclusions: TMZ was well tolerated without major toxicities and had a good RR in pts who had previously failed TMZ. Durable responses were observed in patients who had not initially responded to front-line TMZ. These data suggest that rechallenge with TMZ in previous responders and non-responders warrants further investigation in a prospective study. No significant financial relationships to disclose.

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