A retrospective analysis of selective internal radiation therapy (SIRT) with yttrium-90 microspheres in patients with unresectable hepatic malignancies.

AIM: To evaluate the efficacy and safety of selective internal radiation therapy (SIRT). MATERIALS AND METHODS: A retrospective analysis was undertaken of all patients who underwent SIRT at a single institution. Diagnostic and therapeutic angiograms, computed tomography (CT) images, positron-emission tomography (PET) images, and planar isotope images were analysed. The response to SIRT was analysed using radiological data and tumour markers. Overall survival, complications, and side effects of SIRT were also analysed. RESULTS: The initial 12 patients were included on an intention-to-treat basis, between 21/09/2005 and 07/05/2008. All patients had advanced disease and multiple prior courses of chemotherapy. One patient did not receive yttrium-90 due to complex vascular anatomy; the remaining 11 patients underwent 13 SIRT treatment episodes following work-up angiography. A response was seen using PET in 80% of patients. Using CT, the response of the tumour to therapy in the treated hepatic segments demonstrated a 20% partial response, stable disease in 50%, and progressive disease in 30%. Estimated median survival was 229 days, with 64% of patients still alive at the time of writing. No major complications were observed, although 82% of patients experienced side-effects following SIRT, mainly nausea, vomiting, and abdominal pain. CONCLUSIONS: There have been no complications in the 12 SIRT patients. Tumour response was seen in four out of five patients who underwent PET. Objective CT response rates were mixed and are perhaps partially explained by advanced disease and limitations of using measurements to assess response. This complex and potentially hazardous service has been successfully and safely established.

Long-term experience of pegvisomant therapy as a treatment for acromegaly.

AIMS: To evaluate the long-term efficacy and safety of pegvisomant as a treatment for acromegaly. DESIGN: Retrospective analysis of clinical and trial data from all patients treated with pegvisomant since 1997 at two centres with common protocols. RESULTS: Fifty-seven patients (age range 27-78 years) have been treated with pegvisomant since 1997 for up to 91 months (median 18 months). Before commencing pegvisomant, patients had an IGF-I above the upper limit of normal (ULN) of the age-related reference range (median 1.8 x ULN, range 1.2-4.1). Ninety-five per cent normalized IGF-I using a median dose of 15 mg daily (range 10 mg alternate day to 60 mg daily) with no influence of gender on dose requirement. Five patients had combination therapy with either somatostatin analogues (SSA) or cabergoline. Two patients initially controlled on 10 mg and 20 mg required dose increases (to 20 mg + 40 mg) over 24 months to reduce IGF-I. Twenty-seven patients stopped pegvisomant. Reasons included side-effects [abnormal liver function tests (LFTs)] and patient choice. Two patients developed elevated liver transaminases, which normalized on stopping pegvisomant. Patients had 6-12-monthly pituitary magnetic resonance imaging (MRI) scans. One patient had significant tumour size increase. CONCLUSION: This long-term experience in 57 patients indicates pegvisomant to be effective, safe and well-tolerated. Raised transaminases occurred within the first month of therapy in two patients, and tumour growth was seen in one patient (tumour was growing prior to pegvisomant). In two patients increasing doses of pegvisomant were required to keep IGF-I within the target range.

Phase I evaluation of CDP791, a PEGylated di-Fab' conjugate that binds vascular endothelial growth factor receptor 2.

PURPOSE: Specific blocking of vascular endothelial growth factor receptor 2 (VEGFR-2) is a novel therapeutic approach. Here, we report the first phase I clinical trial evaluation of CDP791, a PEGylated di-Fab' conjugate that binds VEGFR-2. EXPERIMENTAL DESIGN: Cohorts of patients received CDP791 at doses between 0.3 and 30 mg/kg every 3 weeks for the initial two doses. RESULTS: The compound was well tolerated with no dose-limiting toxicity. Dose-related hypertension was observed in patients receiving CDP791 10 mg/kg or more and several patients on the higher doses developed infusion-related cutaneous hemangiomata arising 28 to 106 days after the first drug administration and resolving 3 weeks after cessation. Biopsy and histologic evaluation showed that CDP791-bound VEGFR-2 is non-phosphorylated, suggesting that the drug is biologically active. Concentrations of CDP791 considered biologically relevant were sustained for 3 weeks when doses of 10 mg/kg or more were administered. Although no reductions in vascular permeability were recorded using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), there was a significant dose level-related reduction in tumor growth. While challenging the recent dogma that active VEGF inhibitors should modulate DCE-MRI measurements of vascular permeability, this highlights the potential of serial three-dimensional tumor measurements to detect tumor growth arrest. Twelve patients received drug for more than two treatments, although no partial or complete responses were seen. CONCLUSION: The data show that CDP791 is biologically active and well tolerated, achieving appropriate plasma concentrations when administered at 10 mg/kg or more every 3 weeks.

Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume.

PURPOSE: CDP860 is an engineered Fab' fragment-polyethylene glycol conjugate, which binds to and blocks the activity of the beta-subunit of the platelet-derived growth factor receptor (PDGFR-beta). Studies in animals have suggested that PDGFR-beta inhibition reduces tumor interstitial fluid pressure, and thus increases the uptake of concomitantly administered drugs. The purpose of this study was to determine whether changes in tumor vascular parameters could be detected in humans, and to assess whether CDP860 would be likely to increase the uptake of a concurrently administered small molecule in future studies. PATIENTS AND METHODS: Patients with advanced ovarian or colorectal cancer and good performance status received intravenous infusions of CDP860 on days 0 and 28. Patients had serial dynamic contrast-enhanced magnetic resonance imaging studies to measure changes in tumor vascular parameters. RESULTS: Three of eight patients developed significant ascites, and seven of eight showed evidence of fluid retention. In some patients, the ratio of vascular volume to total tumor volume increased significantly (P < .001) within 24 hours following CDP860 administration, an effect suggestive of recruitment of previously non-functioning vessels. CONCLUSION: These observations suggest that inhibition of PDGFR-beta might improve delivery of a concurrently administered therapy. However, in cancer patients, further exploration of the dosing regimen of CDP860 is required to dissociate adverse effects from beneficial effects. The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.

Assessment and significance of mediastinal bulk in Hodgkin's disease: comparison between computed tomography and chest radiography.

PURPOSE: In Hodgkin's disease (HD), mediastinal bulk is currently defined from chest radiograph (CXR) measurements as a ratio of the maximum transverse mass diameter to the internal thoracic diameter at T5/6 level > or = 0.33. We evaluated how computed tomographic (CT) measurements of bulk correspond to those obtained from the CXR and correlated nodal mass long axis diameter with freedom from progression. METHODS: Ninety-five adult patients who had a CXR thoracic ratio of greater than 0.3 and a CT scan within 28 days of the CXR were included in the study, provided that both investigations were performed before the start of treatment. Measurements of the widest mediastinal diameter and internal thoracic diameter were made on both CXR and CT scan. The thoracic ratio (TR) was calculated for each modality and compared using paired t tests. The longest diameter of the largest individual nodal mass (LIM(CT)) was also measured from the CT and correlated with freedom from progression using Cox regression. RESULTS: There was excellent correlation between CT and CXR for measurement of TR, with TR(CT) greater than TR(CXR) (mean difference of 2%). A TR(CT) of 0. 35 was found to be equivalent to a TR(CXR) of 0.33. No single measurement of nodal size correlated with the current definition of bulk. However LIM(CT) greater than 10 cm did correlate with increased risk of progressive HD (P =.03), even after adjustment for other prognostic variables (chemotherapy regimen and Hasenclever Prognostic Index). CONCLUSION: Excellent correlation was observed between assessment of TR by CXR and CT scan. The longest diameter of the LIM(CT) greater than 10 cm was found to be associated with an increased risk of disease progression.

Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin's lymphoma.

PURPOSE: An open-label phase II study was conducted at two centers to establish the efficacy and safety of tositumomab and iodine I 131 tositumomab at first or second recurrence of indolent or transformed indolent B-cell lymphoma. PATIENTS AND METHODS: A single dosimetric dose was followed at 7 to 14 days by the patient-specific administered radioactivity required to deliver a total body dose of 0.75 Gy (reduced to 0.65 Gy for patients with platelets counts of 100 to 149 x 10(9)/L). Forty of 41 patients received both infusions. RESULTS: Thirty-one of 41 patients (76%) responded, with 20 patients (49%) achieving either a complete (CR) or unconfirmed complete remission [CR(u)] and 11 patients (27%) achieving a partial remission. Response rates were similar in both indolent (76%) and transformed disease (71%). The overall median duration of remission was 1.3 years. The median duration of remission has not yet been reached for those patients who achieved a CR or CR(u). Eleven patients continue in CR or CR(u) between 2.6+ and 5.2+ years after therapy. Therapy was well tolerated; hematologic toxicity was the principal adverse event. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia were observed in 5%, 45%, and 32% of patients, respectively. Secondary myelodysplasia has occurred in one patient. Four patients developed human antimouse antibodies after therapy. Five of 38 assessable patients have developed an elevated thyroid-stimulating hormone; treatment with thyroxine has been initiated in one patient. CONCLUSION: High overall and CR rates were observed after a single dose of tositumomab and iodine I 131 tositumomab in this patient group. Toxicity was modest and easily managed.

Symptoms of colorectal liver metastases: correlation with CT findings.

AIM: To correlate CT appearances of colorectal liver metastases (LM) with pattern and severity of symptoms. MATERIALS AND METHODS: One hundred and twenty patients with treated primary colorectal carcinoma were prospectively assessed by questionnaire for recent symptoms when attending for CT examination. Thorax, abdomen and pelvic CT scans were prospectively assessed for LM and extrahepatic disease (EHD). The number of LM, percentage liver replaced by LM and distribution of LM were recorded. RESULTS: Patients' ages ranged from 35 to 89 years (median 60) and 74/120 (62%) were male. Four subgroups were compared: group 1 - LM only (n = 30); 2 - EHD only (n = 22); 3 - both LM and EHD (n = 28); 4 - neither LM/EHD (n = 40). Anorexia was significantly worse in gp2 vs gp4 (P = 0.016) and lower abdominal pain (LAP) was significantly worse in gp2 vs gpl (P = 0.019). General pain was the worse symptom in all groups but notstatistically greater in any group. Patients with more than 10 LM had significantly worse anorexia (P = 0.002). general pain (P < 0.001) and LAP (P = 0.001). There was a trend (P > 0.05) towards worse symptoms with either volume of diseased liver or subcapsular LM. CONCLUSION: With increasing liver tumour burden there was an increase in symptomatology but extrahepatic abdominal metastatic tumour produced more symptoms than LM alone. Symptoms, particularly pain, therefore are not good predictors of hepatic metastatic disease.

Changes in arterial stiffness but not carotid intimal thickness in acromegaly.

CONTEXT: Acromegaly increases cardiovascular morbidity. We tested the hypothesis that increased arterial stiffness together with left ventricular hypertrophy may be a contributory factor. PATIENTS AND DESIGN: Fifty-six patients (40 males, 54 ± 13 yr; 25 active disease, 31 in remission) and 46 healthy controls (30 males, 52 ± 13 yr) underwent measurements of aortic pulse wave velocity (PWV), carotid Doppler (IMT), echocardiography, and cardiovascular risk factors. RESULTS: Mean serum IGF-I was 323 ± 286 ng/ml (sd score 1.8 ± 1.9) in all patients. Age, body mass index, diastolic blood pressure (BP), and lipid levels were similar comparing patients and controls. Systolic BP (130.8 ± 19.9 vs. 122 ± 14 mm Hg controls, P < 0.01) and PWV (11.7 ± 3.8 vs. 9.7 ± 2.8 m/sec, 95% confidence interval -3.4 to -0.7, P <0.01) were higher in patients than controls. Regression analysis revealed age, presence of acromegaly, systolic BP, and body mass index, inversely, as significantly and independently associated with PWV. No difference in carotid IMT was seen (0.8 ± 0.2 patients vs. 0.7 ± 0.2 mm controls, P = 0.5) or between active/controlled disease. In the subset of participants with echocardiography (n = 32), left ventricular mass was higher by a mean of 38.2 g (95% confidence interval -80.9 to +4.6, P = 0.08). CONCLUSION: In summary, patients with acromegaly had independently and significantly increased aortic PWV as evidence of arterial stiffening but unaltered carotid IMT compared with controls, also influenced by age and systolic BP. Premature cardiovascular disease in patients with acromegaly is likely related to pressure-related arterial and left ventricular stiffening rather than atherosclerotic disease.

Nurse-led central venous catheter service: Christie experience.

The aim of this study was to evaluate the success and complication rate of Nurse-led subclavian central venous catheter (CVC) insertion using the landmark technique. A prospective study was performed on all subclavian CVC insertion between 13/01/03 to 01/07/03. Data recorded included indication for catheter insertion, type of catheter, complications during the procedure and patient satisfaction. A total of 348 subclavian cuffed tunnelled catheters were inserted over the study period. The age group ranged from 31 years to 84 years with a mean age of 53 years. This included 192 women and 156 men. The majority of CVC insertions were through the right subclavian (79%) and were single lumen (76%). In total, complications were encountered in 48 patients (14%). These included misplaced tip in 29 (8%), arterial puncture in 16 (4%), pneumothorax in 3 (1%) and the procedure failed in 3 (1%). Of these multiple complications were seen in 3 (1%). No interventions were required for the pneumothoraces or for the arterial punctures. In conclusion, nurse-led subclavian CVC placements using the landmark technique are both safe and effective.

Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma.

Histamine inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). Two randomised phase II trials of IL-2 with or without histamine dihydrochloride (HDC) in patients with metastatic renal cell carcinoma (mRCC) were run in parallel. A total of 41 patients were included in Manchester, UK and 63 in Aarhus, Denmark. The self-administered, outpatient regimen included IL-2 as a fixed dose, 18 MIU s.c. once daily, 5 days per week for 3 weeks followed by 2 weeks rest. Histamine dihydrochloride was added twice daily, 1.0 mg s.c., concomitantly with IL-2. A maximum of four cycles were given. The Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P = 0.03), a trend towards benefit in both median survival (18.3 vs 11.4 months, P = 0.07), time to PD (4.5 vs 2.2 months, P = 0.13) and clinical benefit (CR + PR + SD) (58 vs 37%, P = 0.10) in favour of IL-2/HDC, whereas the UK study was negative for all end points. Only three patients had grade 4 toxicity; however, two were fatal. A randomised phase III trial is warranted to clarify the potential role of adding histamine to IL-2 in mRCC.

MRI diagnosis of partial tears of the anterior cruciate ligament.

In an attempt to define the magnetic resonance imaging (MRI) features of partial tears of the anterior cruciate ligament (ACL) we retrospectively analysed the MRI scans of 30 patients with a recent arthroscopic finding of a normal, a partial or a completely torn ACL. On review of the original reports MRI correctly predicted 9/9 (100 per cent) complete ACL tears, 11/12 (92 per cent) normal ACLs but only 1/9 (11 per cent) partial ACL tears. On analysis of the MRI there were four features which helped to differentiate partial ACL tears from either complete ACL tears or normal ligaments. These were the appearance of some intact fibres, thinning of the ligament, a wavy or curved ligament and the presence of an inhomogeneous mass posterolateral to the ACL. We propose that these findings may be indicators of partial ACL tear.

The role of ultrasound-guided fine-needle aspiration biopsy in the previously treated patient with thyroid cancer.

The aim of the present study was to evaluate the effectiveness of ultrasound-guided fine-needle aspiration in detecting locoregional recurrence in previously treated patients with thyroid cancer. A retrospective analysis of ultrasound-guided fine-needle aspiration (FNA) biopsy was carried out for suspected recurrence of thyroid cancer over a 5-year period at a single institution. There were 37 biopsies in 37 patients. Each patient's ultrasound report, cytology report and medical notes were examined to determine the result of the biopsy and the patient's outcome. There were 29 true-positives, 6 true-negatives, 1 false-negative and 1 inadequate biopsy. Ultrasound-guided FNA, therefore, had a sensitivity of 96.7%, specificity of 100% and overall accuracy of 97.2% in detecting recurrence. Ultrasound-guided FNA is an accurate method of identifying suspected recurrence.

To clot or not to clot? That is the question in central venous catheters.

AIM: To establish the relationship between the tip position of tunnelled central venous catheters (CVC) and the incidence of venous thrombosis. MATERIALS AND METHODS: A randomly sampled, retrospective review of 428 CVC inserted into 334 patients was performed. The chest radiograph obtained post-catheter insertion, as well as follow-up radiographs, linograms, venograms and Doppler ultrasounds (US), were reviewed. RESULTS: The median follow-up was 72 days (range 1-720 days), with a total follow-up of 23,040 line days. Venous thrombosis occurred in five out of 191 (2.6%) CVC in a distal position (distal third of the superior vena cava (SVC) or right atrium (RA)), five of 95 (5.3%) in an intermediate position (middle third of the SVC) and 20 of 48 (41.7%) in a proximal position (proximal third SVC or thoracic inlet veins). There was a significant difference in thrombosis rate between lines sited with the tip in a distal compared with a proximal position (p<0.0005). CVC with tips in a proximal position were 16 times more likely to thrombose than those in a distal position. None of the 58 CVC with the tip located in the RA thrombosed or caused complications. CONCLUSION: Distal placement of tunnelled CVC, either in the distal third of the SVC or proximal RA is optimal.

Colonic preparation with Picolax: patient tolerance and approaches to fluid replacement.

Sodium picosulphate (Picolax) is widely used for bowel preparation prior to colonic investigation or surgery. The most troublesome side effect reported is headache, which has been thought to be due to dehydration. In a prospective randomized study we investigated the incidence of adverse effects in patients given Picolax prior to barium enema examination, and assessed the incidence of adverse effects with different oral fluid regimens. A total of 197 outpatients were allocated to one of five fluid regimens on the day prior to the enema: (a) 4 pints of Dioralyte (glucose and electrolyte solution); (b) 4 pints of half-strength Dioralyte; (c) 4 pints of water; (d) 6 pints of water; and (e) free fluids. In a questionnaire, 36% of patients had no headache (graded 0/5), while 38% had a significant headache (graded 3/5 or greater). Sixteen per cent had significant abdominal pain, 42% had dry mouths, 43% thirst and 34% tiredness or irritability. There was no correlation between headache and fluid regimen. Furthermore, we have found no evidence of dehydration. None of the five fluid regimens was shown to offer any advantage, and we therefore recommend that patients be allowed to drink according to thirst when taking Picolax.

Staging of advanced cervical carcinoma using MRI-predictors of outcome after radical radiotherapy.

AIM: To assess the prognostic significance of imaging findings used in magnetic resonance imaging (MRI) staging of cervical carcinoma by correlation with survival after radiotherapy. MATERIALS AND METHODS: MRI examinations of 99 cervical carcinoma patients were reviewed. Tumour involvement of pelvic structures was assessed. Lymph node sites, short axis diameters and signal characteristics were recorded. MRI staging was compared with clinical [International Federation of Gynaecology and Obstetrics (FIGO)] staging. Univariate analysis was performed for MRI stage, clinical stage, nodal status and pelvic structure involvement against disease-specific (DSS) and disease-free survival (DFS). RESULTS: MRI staging correlated with DSS (p=0.006) and DFS (p=0.007) but clinical staging did not. Pelvic nodes > or = 10 mm and juxtaregional or distant nodes > or = 8 mm short axis were most strongly associated with survival (p=0.014, p=0.011 and p=0.001, respectively, for association with DSS). Tumour involvement of pelvic bowel loops, pelvic sidewall and bladder mucosa were significantly associated with poor DSS and DFS (p<0.05). Tumour dimensions and bladder muscle involvement alone were not associated with poor survival. CONCLUSION: MRI staging is a better predictor of survival than clinical staging in patients receiving radiotherapy for cervical carcinoma. MRI assessment of lymph node enlargement and tumour involvement of pelvic structures gives valuable prognostic information.

Zebra pattern: a diagnostically challenging hepatic parenchymal enhancement pattern at CT arterial portography.

PURPOSE: To investigate the effect of arterial injection site and splenic volume on the hepatic zebra pattern seen at computed tomographic (CT) arterial portography. MATERIALS AND METHODS: Images from CT arterial portographic examinations, performed via either the splenic artery (SA)(n = 47) or superior mesenteric artery (SMA)(n = 51) in 98 patients, were reviewed. The hepatic parenchymal enhancement pattern was assessed by three blinded reviewers. Splenic volume was determined. RESULTS: Twenty-two of 98 (22%) CT arterial portographic studies showed a zebra pattern: 10 of 47 (21%) with injection via the SA and 12 of 51 (24%) with injection via the SMA. The mean percentage of hepatic parenchyma with nontumorous perfusion defects was 55% with the zebra pattern versus 12% without (P < .001). For SA injections, the mean splenic volume was lower in patients with the zebra patterns (321 vs 409 cm3, P = .09). For SMA injections, it was higher in patients with zebra patterns (372 vs 291 cm3, P = .10). CONCLUSION: The zebra pattern can cause difficulties in interpreting images. It is due to alternating, well-defined regions of portal venous hyper- and hypoperfusion; it likely has a multifactorial cause and is likely due to technical parameters such as the injection site, the volume of the spleen, and the hemodynamic effects of the tumor.

CT during arterial portography: comparison of injection into the splenic versus superior mesenteric artery.

PURPOSE: To determine whether the diagnostic quality of computed tomography (CT) during arterial portography (CTAP) performed via the splenic artery (SA) is better than that performed via the superior mesenteric artery (SMA). MATERIALS AND METHODS: The authors evaluated CTAP images obtained in 98 patients from 1991 to 1994; 47 examinations were performed via the SA and 51 were performed via the SMA. Images were reviewed, by consensus, by three radiologists blinded to catheter location. Hepatic enhancement was quantitatively assessed in 53 patients (31 in the SA group, 22 in the SMA group). RESULTS: The numbers of low-attenuation non-tumor-related perfusion defects (19 in the SA group, 17 in the SMA group), high-attenuation non-tumor-related perfusion defects (six in the SA group, six in the SMA group), diffuse mottled perfusion abnormalities (six in the SA group, five in the SMA group), and portal venous flow defects (20 in the SA group, 20 in the SMA group) were similar in both groups (P > .05). Peak hepatic enhancement was similar in both groups (SMA group = 111 HU; SA group = 112 HU) (P > .05). CONCLUSION: There is no difference in quality between CTAP performed via the SA versus CTAP performed via the SMA.

Gastrostomy insertion: comparing the options--PEG, RIG or PIG?

AIM: To compare percutaneous endoscopic gastrostomy (PEG) with radiologically inserted gastrostomy (RIG) and assess a hybrid gastrostomy technique (per-oral image-guided gastrostomy, PIG). MATERIALS AND METHODS: Fifty PEGs and 50 RIGs performed in three centres were prospectively compared and the endoscopic findings of 200 PEGs reviewed. A fluoroscopy-guided technique was modified to place 20 F over-the-wire PEG-tubes in 60 consecutive patients. RESULTS: Technical success was 98%, 100% and 100% for PEG, RIG and PIG, respectively. Antibiotic prophylaxis significantly reduced stoma infection for orally placed tubes (p=0.02). Ten out of 50 (20%) small-bore RIG tubes blocked. Replacement tubes were required in six out of 50 PEGs (12%), 10 out of 50 RIGs (20%), but no PIGs (p<0.001). No procedure-related complications occurred. The function of radiologically placed tubes was significantly improved with the larger PIG (p<0.001), with similar wound infection rates. PIG was successful in 24 patients where endoscopic insertion could not be performed. Significant endoscopic abnormalities were found in 42 out of 200 PEG patients (21%), all related to peptic disease. Insignificant pathology was found in 8.5%. CONCLUSION: PIG combines advantages of both traditional methods with a higher success and lower re-intervention rate. Endoscopy is unlikely to detect clinically relevant pathology other than peptic disease. PIG is a very effective gastrostomy method; it has better long-term results than RIG and is successful where conventional PEG has failed.