Denosumab in advanced/unresectable giant-cell tumour of bone (GCTB): For how long?

BACKGROUND: Giant-cell tumours of bone (GCTB) are RANK/RANK-ligand (RANKL) positive, aggressive and progressive osteolytic tumours. Denosumab, a RANKL inhibitor, was FDA-approved for adults and skeletally mature adolescents with unresectable GCTB or when surgical resection is likely to result in severe morbidity. Data on long-term toxicity and activity of denosumab monthly 'GCTB-schedule' (120 mg per 12/year, 1440 mg total dose/year) are lacking. METHODS: Patients with GCTB receiving denosumab, 120 mg on days 1, 8, 15, 29 and every 4 weeks thereafter, from 2006 to 2015 treated in two centres were included. Long-term toxicity was evaluated. RESULTS: Ninety-seven patients were identified. 43 patients underwent resection of the tumour with a median time on denosumab treatment of 12 months (range 6-45 months). Fifty-four patients had unresectable GCTB's (male/female 23/31, median age 35 years [range: 13-76 years], 26% presented with lung metastases, 31% had primary tumor located to the spine, 63% were relapsed after previous surgery) with a median time on denosumab of 54 months (9-115 months). In the unresectable GCTB group, tumour control and clinical benefits were observed in all patients undergoing denosumab, whereas 40% of patients discontinuing denosumab had tumour progression after a median of 8 months (range 7-15 months). ADVERSE EVENTS: Overall, six (6%) patients developed osteonecrosis of jaw (ONJ): 1/43 (2%) in the resectable group, 5/54 (9%) in the unresectable group, with a 5-year ONJ-free survival of 92% (95% CI 84-100). Only patients with prolonged treatment experienced mild peripheral neuropathy (6/54, 11%), skin rash (5/54, 9%), hypophosphataemia (2/54, 4%) and atypical femoral fracture (2/54, 4%). CONCLUSIONS: Prolonged treatment with denosumab has sustained activity in GCTB, with a mild toxicity profile. The dose-dependent toxicity observed recommends a careful and strict monitoring of patients who need prolonged treatment. Decreased dose-intensity schedules should be further explored in unresectable GCTB.

Early Results of Physician Modified Fenestrated Stent Grafts for the Treatment of Thoraco-abdominal Aortic Aneurysms.

OBJECTIVES: The aim was to determine whether physician modified stent grafts (PMSGs) are safe and effective for the treatment of high risk patients with thoraco-abdominal aortic aneurysms (TAAAs). DESIGN: This was a retrospective single institution study. MATERIAL: Consecutive patients with TAAA undergoing endovascular repair using a PMSG between January 2012 and June 2014 were evaluated. METHODS: Fenestrations to preserve branch vessels were created in TX2 thoracic (Cook Medical) stent grafts. Pre- intra- and post-operative data were recorded by means of a prospectively maintained database. RESULTS: Eleven high risk patients with TAAA (type I, n = 4; type III, n = 3; type IV, n = 3; type V, n = 1) underwent fenestrated endovascular repair using PMSGs. Indications were painful aneurysm (n = 5), >70 mm rapidly enlarging aneurysm (n = 4), saccular aneurysm (n = 1), and visceral patch false aneurysm after open repair of a type IV TAAA (n = 1). In four asymptomatic patients, an additional fenestration was created for temporary selective sac perfusion and occluded 2-4 weeks later. Median duration for stent graft modifications was 2 hours (range 1-3 hours). The median number of fenestrations was three (range 2-4). One patient died during the post-operative period from colonic ischemia, giving a 9% in hospital mortality rate. Four (36%) patients presented with moderate to severe complications. One (9%) patient presented with a paraparesis that resolved completely after spinal fluid drainage. Among surviving patients, four required early endovascular re-intervention for type III endoleak (n = 2), type Ia endoleak (n = 1), or target vessel cannulation failure (n = 1). The median follow up time was 6 months (range 3-20 months). During follow up, no other complications occurred and all target vessels remained patent. One patient presented with a persistent type II endoleak. CONCLUSION: PMSGs provided acceptable short-term results and may be a management option for the treatment of TAAA in selected high risk patients. Durability concerns need to be assessed in additional studies with long-term follow up.

An anatomical review of spinal cord blood supply.

Knowledge of the spinal cord (SC) vascular supply is important in patients undergoing procedures that involve the thoracic and thoracoabdominal aorta. However, the SC vasculature has a complex anatomy, and teaching is often based only on anatomical sketches with highly variable accuracy; historically, this has required a "leap of faith" on the part of aortic surgeons. Fortunately, this "leap of faith" is no longer necessary given recent breakthroughs in imaging technologies and postprocessing software. Imaging methods have expanded the non-invasive diagnostic ability to determine a patient's SC vascular pattern, particularly in detecting the presence and location of the artery of Adamkiewicz. CT is the imaging modality of choice for most patients with thoracic and thoracoabdominal aortic disease, proving especially useful in the determination of feasibility and planning of endovascular treatment. Thus the data set required for analysis of SC vascular anatomy is usually already available. We have concentrated our efforts on CT angiography, which offers particularly good imaging capabilities with state-of-the-art multidetector scanners. Multidetector row helical CT provides examinations of an extensive range in the craniocaudal direction with thin collimation in a short time interval, giving excellent temporal and spatial resolution. This paper provides examples of the SC vasculature imaging quality that can be obtained with 64 row scanners and appropriate postprocessing. Knowledge of the principal anatomical features of the SC blood supply of individual patients undergoing open or endovascular thoracoabdominal procedures has several potential benefits. For open surgery, analysis of the SC vasculature could tell us the aortic region that feeds the Adamkiewicz artery and thus needs to be reimplanted. For endovascular procedures, we can determine whether the stent-graft will cover the Adamkiewicz artery, thus avoiding unnecessary coverage. CT data can also be used to stratify risk of SC ischemia and guide the selective use of spinal cord injury prevention strategies.

Strategies to treat thoracic aortitis and infected aortic grafts.

Infectious thoracic aortitis is a rare disease, especially since the incidence of syphilis and tuberculosis has dropped in western countries. However, the risk to develop an infectious aortitis and subsequent mycotic aneurysm formation is still present, particularly in case of associated endocarditis, sepsis, and in immunosuppressive disorders. Moreover, the number of surgical and endovascular thoracic aortic repairs is continuously increasing, and infective graft complications are observed more frequently. Several etiopathogenetic factors may play a role in thoracic aortic and prosthetic infections, including hematogenous seeding, local bacterial translocation, and iatrogenous contamination. Also, fistulization of the esophagus or the bronchial tree is commonly associated with these diseases, and it represents a critical event requiring a multidisciplinary management. Knowledge on underlying micro-organisms, antibiotic efficacy, risk factors, and prevention strategies has a key role in the management of this spectrum of infectious diseases involving the thoracic aorta. When the diagnosis of a mycotic aneurysm or a prosthetic graft infection is established, treatment is demanding, often including a number of surgical options. Patients are usually severely compromised by sepsis, and in most cases they are considered unfit for surgery for general clinical conditions or local concerns. Thus, results of different therapeutic strategies for infectious diseases of the thoracic aorta are still burdened with very high morbidity and mortality. In this manuscript, we review the literature regarding the main issues related to thoracic infectious aortitis and aortic graft infections, and we report our personal series of patients surgically treated at our institution for these conditions from 1993 to 2014.

Effectiveness of Zilver PTX eluting stent in TASC C/D lesions and restenosis.

AIM: The indication for use of drug-eluting stents (DES) in lower limb arteries is still undefined. We report our series of patients treated with Zilver PTS DES, in treating in-stent restenosis (ISR) and Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease (TASC) C/D femoropopliteal lesions. METHODS: The Zilver PTX DES is a self-expanding nitinol stent with a polymer-free Paclitaxel coating. Patients with symptomatic de novo TASC C/D lesions or IRS lesions of femoropopliteal segment were eligible for enrollment. We evaluated patients at one month, six months and one year after treatment. We used clinical evaluation criteria and US Doppler for primary and secondary patency-free rates. RESULTS: From November 2010 to November 2012, we treated 69 patients with DES Zilver PTX. Indication to treat was given in 36 lesions (52%) by an ISR and in 33 cases (48%) by a TASC C/D lesion. Lesions were staged in the superficial femoral artery (SFA) level in 59 patients (85.6%), in the popliteal artery in 6 patients (8.7%), in a femoropopliteal bypass in 4 patients (5.7%). The mean follow-up was 5.3 months (range 1-24). At 12 months the overall primary patency was 85.5%, secondary patency 89.8% and limb salvage 100%. CONCLUSION: Zilver PTX DES seems to be effective in treating TASC C/D lesions and ISR in femoropopliteal lesions at short term. Therefore DES should be recommended when treating those complex lesions.

Subjects with obstructive pulmonary disease tend to be chronically vasodilated.

1. In 12 unselected outpatients with chronic obstructive pulmonary disease and six controls, arterial pH, PaO2, PaCO2 and oxygen saturation (SaO2), forced expiratory volume in 1.0 s (FEV1.0) and vital capacity were measured. Subjects were grouped into those with or without obstruction based on the Tiffenau index. The Baseline Dyspnoea Index was employed to objectify the severity of dyspnoea and the Borg index to evaluate the subjective sensation. Blood pressure was measured with a sphygmomanometer; calf arterial flow both at rest and during reactive hyperaemia with a plethysmograph. Basal and minimal resistance were calculated.2.FEV1.0 was 26% lower in patients with obstruction than in controls, and was also lower in patients with moderate-to-severe obstruction compared with those with mild or no obstruction. Arterial flow (75% greater in the patients with obstruction) progressively increased with increasing severity of obstruction, being 54% higher in those with mild obstruction than in those with no obstruction (P<0.001), and 28% higher in moderate-severe than in mild obstruction (P<0.005). In multiple regressions, F correlated inversely with FEV1.0, PaO2 and SaO2, and directly with PaCO2. Basal resistance correlated positively with FEV1.0, SaO2 and the Tiffenau index, and inversely with PaCO2 (r=-0.52, P=0.02). Minimal resistance was significantly lower in obstructed than in non-obstructed subjects. Both basal and minimal resistance progressively decreased, although insignificantly, with worsening bronchial obstruction. PaCO2 did not correlate with any haemodynamic parameter. Borg index correlated indirectly with FEV1.0 and basal resistance directly with arterial flow.3. Patients with chronic obstructive pulmonary disease therefore tend to show chronic vasodilatation depending on hypoxia rather than PaCO2. Other mechanisms could be involved in this phenomenon. The Borg index is a good indicator of oxygen desaturation and vasodilatation.

Tolerability and antihypertensive efficacy of Fosinopril on 24-hr ambulatory blood pressure in hypertensive elderly subjects.

The tolerability and antihypertensive efficacy of Fosinopril were assessed in 34 elderly patients with mild to moderate hypertension. Twenty-four-hour ambulatory blood pressure (BP) was measured before and after 5 months of therapy. The patients' mean age was 67 years. At the end of the treatment the mean 24-hour systolic BP (SBP) fell from 153.4 +/- 14 to 137.7 +/- 13 mmHg and the mean 24-hour diastolic BP from 91 +/- 11 to 84.2 +/- 9 mmHg (p < 0.01). The mean decrease in SBP was 15.9 mmHg during the day and 10.3 during the night, and in diastolic BP (DBP) 8.3 mmHg during the day and 10.3 mmHg during the night (p < 0.05 between day and night). There was no significant percentage difference between the SBP and DBP decreases. The mean morning maximum of SBP decreased from 171 +/- 18 to 158 +/- 19 mmHg and there was a reduction in pressure increase between the night and day. The number of SBP peaks over 180 mmHg and 160 mmHg numerically decreased to 20.1% and 37.6% versus baseline, those of DBP over 105 mmHg and 95 mmHg to 41.6% and 58.3% versus baseline, respectively. There were no variations in the blood chemistry parameters and the drug had no adverse side effects. The authors conclude that Fosinopril is useful and well tolerated in the treatment of moderate hypertension in the elderly.

Gall stone pulverisation strategy in patients treated with extracorporeal lithotripsy and follow up results of maintenance treatment with ursodeoxycholic acid.

Between November 1988 and July 1992 70 patients with radiolucent gall stones were treated with extracorporeal lithotripsy (ESL) and ursodeoxycholic acid (UDCA; mean (SD) dose 11.2 (1.9) mg/kg/day). Fifty three patients have been followed for one year. One week after lithotripsy, 30.6% had completely eliminated all stone fragments from the gall bladder and one year later 93.9% were free of stones. Three factors were considered important in achieving these results. 'Pulverisation' of the stone--that is, its fragmentation into echogenic dust (crystalline aggregates, some few hundred mu in size) or particles similar to grains of sand, smaller than 1 mm in diameter, or both, is required. Secondly, dust and particles were rapidly eliminated, strongly suggesting a mechanical elimination process by physiological gall bladder contractions. Thirdly, there must be chemical dissolution with biliary acids. This therapeutic approach gave excellent results without causing any clinically relevant side effects. The first 20 patients who became free of stones after ESL were given oral bile acid maintenance treatment--300 mg/day of UDCA at bedtime, for two years. All were asymptomatic and none had suffered a recurrence after two years. In four patients, crystalline aggregates, detected in gall bladder bile by ultrasound, were subsequently dissolved between one and three months after resuming a full dose regimen of UDCA.

Peptic disease and 24-hr patterns of serum gastrin and pepsinogen.

The present study explored the 24-hr variations in serum gastrin and pepsinogen in clinically healthy subjects and in patients with gastric ulcer, duodenal ulcer, and erosive gastroduodenopathy. Time-qualified data were analyzed by means of cosinor procedures. Significant changes in rhythmometric properties were documented in patients with peptic disease when compared to clinically healthy subjects. In essence, it was discovered that gastric ulcer patients exhibit a higher mesor and amplitude for both gastrin and pepsinogen, whereas duodenal ulcer patients and those with erosive gastroduodenopathy show only a significant increase in the pepsinogen mesor. These characteristics are so specific in the groups investigated that one can hypothesize that the disorders in the circadian rhythmicity of gastrin and pepsinogen have a role in determining the clinical manifestations of peptic disease.