Aflibercept, ranibizumab and bevacizumab upcoming biosimilars: a general overview.

Anti-vascular endothelial growth factors currently are the first-line treatment option for neovascular age-related macular degeneration (nAMD) and other retinal vascular disorders, and their clinical use is associated with high financial burden. Biosimilars are a type of biological product highly similar to referral biologic drugs; they are increasing competition among biologics and have the potential to reduce the overall expenditures on biologics. In this comprehensive literature review, the current investigational biosimilars acting on retinal diseases are discussed. The authors review the results of clinical studies and highlight ongoing trials. Several biosimilar candidates are under evaluation and the pipeline will rapidly change in the future, as soon as each patent expires. Clinicians have to know these new therapeutic agents, which might come in the mainstream clinical practice as a more cost-efficient option.

Management of ventriculomegaly in pediatric patients with syndromic craniosynostosis: a single center experience.

INTRODUCTION: Management of ventriculomegaly in pediatric patients with syndromic craniosynostosis (SC) requires understanding the underlying mechanisms that cause increased intracranial pressure (ICP) and the role of cerebrospinal fluid (CSF) in cranial vault expansion in order to select the best treatment option for each individual patient. METHODS: A total of 33 pediatric patients with SC requiring craniofacial surgery were retrospectively evaluated. Cases of nonsyndromic craniosynostosis and shunt-induced craniosynostosis were excluded. Six syndrome-based categories were distinguished: Crouzon syndrome, Pfeiffer syndrome, Apert syndrome, cloverleaf skull syndrome, and others (Muenke syndrome, Sensenbrenner syndrome, unclassified). All of the patients were treated surgically for their cranial deformity between 2010 and 2016. The presence of ventriculomegaly and ventriculoperitoneal (VP) shunt requirement with its impact in cranial vault expansion were analyzed. Clinical and neuroimaging studies covering the time from presentation through the follow-up period were revised. The mean postoperative follow-up was 6 years and 3 months. A systematic review of the literature was conducted through a PubMed search. RESULTS: Of the total of 33 patients with SC, 18 (54.5%) developed ventriculomegaly and 13 (39.4%) required ventriculoperitoneal (VP) shunt placement. Six patients (18.2%) required shunt placement previous to craniofacial surgery. Seven patients (21.2%) required a shunt after craniofacial surgery. Seven fixed pressure ventriculoperitoneal shunts and six programmable valves were placed as first choice. All patients improved their clinical symptoms after shunt placement. Aesthetic results seemed to be better in patients with programmable shunts. CONCLUSIONS: Unless clear criteria for overt hydrocephalus are present, it is recommended to perform craniofacial surgery as a first step in the management of patients with SC in order to preserve the expansive effect of CSF for cranial vault expansion. In our experience, the use of externally programmable valves allows for the treatment of hydrocephalus while maintaining the expansive effect of CSF for the remodeling of the cranial vault. Prospective evaluations are needed to determine causality.

An update on ripasudil for the treatment of glaucoma and ocular hypertension.

Ripasudil (K-115) is a novel Rho-associated protein kinase (ROCK) inhibitor. The Rho-ROCK pathway regulates key downstream effectors involved in many cellular functions, in particular in the actin cytoskeleton activity. The clinical effects of ripasudil expected on the eye include an intraocular pressure-lowering effect and a wound-healing activity on corneal endothelial cells, but many other functions are currently under investigation. To date, ripasudil has been approved in Japan (2014) for the treatment of glaucoma and ocular hypertension, and several clinical trials are currently investigating its role in the treatment of Fuchs' corneal dystrophy. In this review, we will discuss its pharmacokinetics, pharmacodynamics and clinical efficacy, focusing also on its safety and tolerability profile.

Necessity of therapy for post-thyroidectomy hypocalcaemia: a multi-centre experience.

PURPOSE: Hypoparathyroidism is one of the most common and most feared complications of total thyroidectomy (TT). The aim of this study is to detect possible markers that may facilitate early tracing of hypocalcaemia-prone patients in order to reduce clinical cost by optimizing patient discharge and to avoid unnecessary treatment. METHODS: Over an 18-month period, 995 patients, 23 % male and 77 % female, aged 52.9 ± 13.4 years, underwent TT in ten Lombardy hospitals. The following parameters were analyzed: calcaemia before and 12-24 and 48 h after surgery, pre- and post-operative parathyroid hormone (PTH) at 24 h and pre-operative 25OH vitamin D. RESULTS: Mortality was nil and morbidity was 22.4 %. Mean 24-h calcaemia and PTH were 2.17 ± 0.15 mmol/l and 31.81 ± 20.35 pg/ml, respectively; mean 24-h PTH decay was 36.7 ± 34.12 %. Four hundred seventy-three (47.5 %) patients were hypocalcaemic at discharge; 142 of whom had transient hypoparathyroidism that became permanent in 27. Patients developing hypocalcaemia had significantly higher values of PTH and calcium decay. At multiple logistic regression, only 24-h calcium decay, PTH drop and the presence of symptoms and parathyroid auto-grafting were significantly related to hypoparathyroidism. The association of these factors had a 99.2 % negative predictive value (NPV) for the development of hypoparathyroidism. A 70 % PTH drop had a 93.75 NPV for transient hypoparathyroidism. A 12 % calcaemia decay had a 95.7 NPV for hypoparathyroidism. CONCLUSIONS: Hypocalcaemic asymptomatic patients with less than 70 % PTH and 12 % calcaemia decay may be safely discharged without treatment. Symptomatic patients and those with parathyroid grafting should receive calcium and vitamin D.

Sevoflurane vs. propofol in patients with coronary disease undergoing mitral surgery: a randomised study.

BACKGROUND: Myocardial ischemic damage is reduced by volatile anaesthetics in patients undergoing low-risk coronary artery bypass graft surgery; few and discordant results exist in other settings. We therefore performed a randomised controlled trial (sevoflurane vs. propofol) to compare cardiac troponin release in patients with coronary disease undergoing mitral surgery. METHODS: Patients with coronary artery disease undergoing mitral surgery were randomly allocated to receive either sevoflurane (50 patients) or propofol (50 patients) as main hypnotic. The primary endpoint of the study was peak post-operative cardiac troponin release defined as the maximum value among the post-operative values measured at intensive care unit arrival, 4 h later, on the first and second post-operative day. RESULTS: There was no significant difference in post-operative peak troponin release, the median (25th-75th percentiles) values being 14.9 (10.1-22.1) ng/ml and 14.5 (8.8-17.6) ng/ml in the sevoflurane and propofol groups, respectively (P = 0.4). Fentanyl administration was different between the two groups: 1347 ± 447 µg in patients receiving sevoflurane and 1670 ± 469 µg in those receiving propofol, P = 0.002. The 1-year follow-up identified two patients who died in the propofol group (one myocardial infarction and one low cardiac output syndrome) and one in the sevoflurane group (myocardial infarction). CONCLUSION: In this study, patients with coronary artery disease undergoing mitral surgery did not benefit from the cardioprotective properties of halogenated anaesthetics. Sevoflurane anaesthesia was not associated to lower cardiac troponin release when compared with propofol anaesthesia.

Safety and outcome of surgical debridement of insertional Achilles tendinopathy using a transverse (Cincinnati) incision.

This is a prospective analysis on 30 physically active individuals with a mean age of 48.9 years (35 to 64) with chronic insertional tendinopathy of the tendo Achillis. Using a transverse incision, the tendon was debrided and an osteotomy of the posterosuperior corner of the calcaneus was performed in all patients. At a minimum post-operative follow-up of three years, the Victorian Institute of Sports Assessment scale-Achilles tendon scores were significantly improved compared to the baseline status. In two patients a superficial infection of the wound developed which resolved on antibiotics. There were no other wound complications, no nerve related complications, and no secondary avulsions of the tendo Achillis. In all, 26 patients had returned to their pre-injury level of activity and the remaining four modified their sporting activity. At the last appointment, the mean pain threshold and the mean post-operative tenderness were also significantly improved from the baseline (p < 0.001). In patients with insertional tendo Achillis a transverse incision allows a wide exposure and adequate debridement of the tendo Achillis insertion, less soft-tissue injury from aggressive retraction and a safe osteotomy of the posterosuperior corner of the calcaneum.

GRB 090423 at a redshift of z approximately 8.1.

Gamma-ray bursts (GRBs) are produced by rare types of massive stellar explosion. Their rapidly fading afterglows are often bright enough at optical wavelengths that they are detectable at cosmological distances. Hitherto, the highest known redshift for a GRB was z = 6.7 (ref. 1), for GRB 080913, and for a galaxy was z = 6.96 (ref. 2). Here we report observations of GRB 090423 and the near-infrared spectroscopic measurement of its redshift, z = 8.1(-0.3)(+0.1). This burst happened when the Universe was only about 4 per cent of its current age. Its properties are similar to those of GRBs observed at low/intermediate redshifts, suggesting that the mechanisms and progenitors that gave rise to this burst about 600,000,000 years after the Big Bang are not markedly different from those producing GRBs about 10,000,000,000 years later.

An enigmatic long-lasting gamma-ray burst not accompanied by a bright supernova.

Gamma-ray bursts (GRBs) are short, intense flashes of soft gamma-rays coming from the distant Universe. Long-duration GRBs (those lasting more than approximately 2 s) are believed to originate from the deaths of massive stars, mainly on the basis of a handful of solid associations between GRBs and supernovae. GRB 060614, one of the closest GRBs discovered, consisted of a 5-s hard spike followed by softer, brighter emission that lasted for approximately 100 s (refs 8, 9). Here we report deep optical observations of GRB 060614 showing no emerging supernova with absolute visual magnitude brighter than M(V) = -13.7. Any supernova associated with GRB 060614 was therefore at least 100 times fainter, at optical wavelengths, than the other supernovae associated with GRBs. This demonstrates that some long-lasting GRBs can either be associated with a very faint supernova or produced by different phenomena.

The effects of prolonged peritendinous administration of PGE1 to the rat Achilles tendon: a possible animal model of chronic Achilles tendinopathy.

We studied the effects of peritendinous Achilles tendon injections of prostaglandin E1 (PGE1) on the Achilles tendon of rats. Five groups of Sprague-Dawley rats (n = 24 each) were studied. Groups 1 to 4 received weekly peritendinous injections. In group 1, one side was injected with 800 ng of PGE1 in 0.5 ml of 0.9% NaCl and the contralateral side was injected with 0.5 ml of 0.9% NaCl. In group 2, one side was injected with 800 ng of PGE1. In group 3, one side was injected with 0.5 ml of 0.9% NaCl. In group 4, a syringe needle was inserted in the peritenon unilaterally, but no substances were administered. In groups 2, 3, and 4, the contralateral tendon was used as the control. In group 5, treatment was not administered. Eight rats in each group were killed at each time point, after 7, 21, and 35 days of treatment. On day 7, values for average water content and average wet weight of the tendons treated with PGE1 were significantly higher than those in the control tendons (analysis of variance [ANOVA]; P = 0.02), with a histological picture of acute inflammation. On day 21, approximately half of the PGE1-treated tendons showed fibrosis of the paratenon, with adhesions and intra-tendinous degeneration, with the other half still showing a picture of acute inflammation. On day 35, all of the PGE1-treated tendons showed fibrosis of the paratenon, with adhesions and intra-tendinous degeneration. At all time points, there was no evidence of pathology in the tendons that had not received PGE1. Sham peritendinous injections and injections of normal saline did not produce inflammation in the Achilles tendons. Initially, local administration of PGE1 produced acute inflammation of the tendon and its surrounding tissues. Prolonged PGE1 administration produced peri- and intra-tendinous degeneration, providing a cheap, reproducible model of Achilles tendinopathy, which would allow studies of the effects of conservative and surgical management of the condition.

Recovery of third nerve palsy after endovascular packing of internal carotid-posterior communicating artery aneurysms.

SUMMARY: Endovascular packing of intracranial aneurysm with preservation of the parent vessel has become in many cases a valid alternative to surgical clipping. Regression of oculomotor disorders after clipping of internal carotid-posterior communicating artery (ICA-PCoA) aneurysms has been well assessed. This report focuses on the reversal of third nerve palsy after endovascular packing of ICA-PCoA aneurysms. To this end, clinical appearances, neuroradiological features, and endovascular interventional procedures of six treated patient are reported and discussed in the light of the very few previous case observations found in the literature. Results indicate that endovascular packing of ICA-PCoA aneurysms may produce effective recovery of correlated third nerve dysfunction.

Ultrasound-guided percutaneous longitudinal tenotomy for the management of patellar tendinopathy.

Thirty-eight athletes with unilateral patellar tendinopathy (17 with a tendinopathy of the main body of the tendon, and 21 with an insertional tendinopathy) underwent ultrasound-guided multiple percutaneous longitudinal tenotomy under local anaesthetic infiltration after failure of conservative management. Thirty-four patients were reviewed at least 24 months after the operation. Sixteen patients were rated excellent, nine good, eight fair, and five poor. Nine of the 13 patients with a fair or poor result had an insertional tendinopathy, and eight of them underwent a formal exploration of the patellar tendon. Before the operation, there were some areas of altered echogenicity at and around the site of involvement. These were still visible 6 wk after surgery in 70% of the patients. At the latest follow-up, in the patients with an excellent or good result, the tendon was generally isoechogenic but slightly thicker (P = 0.06) than the normal contralateral. In the patients with a fair or poor result, the tendon was significantly thicker than the contralateral (P = 0.03), and showed some areas of mixed echogenicity. In the patients in whom the procedure was successful, the thicker operated tendon did not interfere with physical training. Bilateral isokinetic peak torque (Nm), average work (Joules), and average power (Watts) were tested at 90 degrees x s(-1). Immediately before the operation, there was no significant difference in peak torque, but total work and average power were significantly lower in the limb to be operated (0.01 < P < 0.05). By the end of the study, although peak torque was, on average, within 7% of the unoperated limb, total work and average power were still significantly lower than in the unoperated limb (0.01 < P < 0.04). Percutaneous longitudinal internal tenotomy is simple, can be performed on an outpatient basis, requires minimal follow-up care, does not hinder further surgery should it be unsuccessful, and, in our experience, has produced no significant complications. In our hands, it has become the first line operative intervention in the treatment of chronic patellar tendinopathy after failure of conservative management. However, patients should be advised that, if they suffer from an tendinopathy at the attachment of the patellar tendon at the lower pole of the patella, a formal surgical exploration with stripping of the paratenon is preferable.

The disappearing exostosis? A report of an unusual case.

A girl aged 11 years was referred to us with a medial upper right tibial exostosis. As the lesion was asymptomatic, surgery was not undertaken. The patient defaulted from follow up, and, when reviewed 32 months later, there was no clinical or radiographic evidence of the exostosis. Spontaneous involution of an exostosis may occasionally occur in childhood.

Results of percutaneous longitudinal tenotomy for Achilles tendinopathy in middle- and long-distance runners.

From August 1989 to January 1995 we performed multiple percutaneous longitudinal tenotomies under local anesthetic on 52 middle- and long-distance runners with unilateral Achilles tendinitis or peritendinitis that had failed conservative treatment. Forty-eight patients were reviewed at an average of 22.1 months (SD, 6.5) after surgery. Results were rated as excellent in 25 patients, good in 12, fair in 7, and poor in 4. Four patients developed subcutaneous hematomas. One patient developed a superficial infection at one of the incision sites, which was managed by oral antibiotics with full recovery. Three patients complained of over-sensitivity to the incisions; this was resolved by rubbing hand cream over the incisions several times a day. One patient developed hypertrophic painful scars on three of the five incisions, but corticosteroid injections yielded good functional and cosmetic results. Isometric strength and endurance of the gastrocsoleus complex was measured just before the procedure, and at 6 weeks and 6 months later. Both were within 10% of the normal contralateral limb by the 6th postoperative month. Percutaneous longitudinal tenotomy is simple, can be performed on an outpatient basis, requires minimal follow-up care, and, in our experience, has produced no significant complications. We use this procedure as the operative treatment of choice for cases of chronic tendinitis that have failed conservative treatment.

Central venous thrombosis: an early and frequent complication in cancer patients bearing long-term silastic catheter. A prospective study.

Studies on catheter-related central venous thrombosis (CRCVT) have been focused mainly on clinically evident CRCVT due to occlusive thrombi, underestimating therefore the actual thrombosis prevalence. This prospective study was aimed at evaluating prevalence, timing and evolution of thrombosis, and identifying involved veins and risk factors in cancer patients (pts) undergoing percutaneous subclavian central venous catheterization (CVC) for chemotherapy, parenteral nutrition or both. We enrolled 127 consecutive pts requiring partially or totally implanted central venous silastic catheters. The study protocol included peripheral phlebography (P) at day 8, 30 and every two months following CVC and/or when clinically indicated, along with peripheral and pullout P on catheter withdrawal. A quantitative scale was developed to evaluate thrombus grading in subclavian, innominate and cava veins. Age, sex, coagulation profile tumor histotype, metastases, therapy, catheter type, and catheter insertion side were also investigated. Only pts who underwent at least two P were evaluated, and chi 2 test was adopted for statistical analysis. Altogether, 95 pts were evaluable. CRCVT was observed in 63/95 (66%) pts. At day 8, 30 and 105 (representing the median days in which first, second and last P were performed) CRCVT was evidenced in 64%, 65% and 66% of the pts, respectively. Thrombus grading did not differ among first, second and last P. CRCVT was symptomatic in 4/63 (6%) pts. Thrombosis prevalence was higher in subclavian (97%) with respect to innominate (60%) or cava (13%) veins (p < 0.001). Thrombosis was higher in left subclavian catheters (14/16; 87.5%) than in right ones (49/79; 62%), p < 0.01. No associations were established between CRCVT and other investigated parameters. Our data show a very high actual frequency of CRCVT in cancer pts, and emphasize that first days following CVC are at the highest risk for CRCVT development. Based on our results, a study on short-term antithrombotic prophylaxis in cancer pts requiring CVC is warranted. Finally, our data indicate that left subclavian vein catheterization represents a risk factor for CRCVT.

[The radon risk in Lombardy]. / Rischio del radon nella Lombardia.

We investigated the geographical distribution of lung cancer mortality rates in some Italian regions, Lombardy and Emilia-Romagna in particular, where the investigation was mainly focused on the risk related to the presence of radon inside dwelling-houses. We referred to the death certificates provided by the Central Institute of Statistics (ISTAT) relative to the years 1980-1988 to calculate the relevant mortality rates. Mortality rates appear higher in some northern than in southern regions and in the islands and also (> a factor of 10) in the male than in the female population; the mortality rates in the male population exhibit a linear correlation with past cigarette smoking. The death rates in the male population (age range: 35-64 years) in northern Italy average 100 events/100,000 inhabitants, but several local health centers in Lombardy at the foot of the Alpine range, north of the Po River, have mortality rates over 50% higher than estimated rates. We considered radon exposure in Lombardy dwelling-houses. The Alps are rich in granite rocks, with 50-150 Bq/kg uranium concentrations, which produce the sediments, sands and gravels making the ground of the Lombardy plain. A recent survey of indoor radon exposure levels showed average values around 100 Bq/m3. The National Academy of Sciences (Washington, DC) has presented a formula to calculate the relative risk of lung cancer related to radon exposure during a lifetime. When this model was applied to excess events in Lombardy, acceptable agreement was found with the assumption that excess deaths are ascribable to higher radon exposure levels. We also compared Lombardy with Emilia-Romagna where the sediments and soil in the plain come from the Apennine range where calcareous rocks have low uranium content. Radon exposure levels in Emilia-Romagna were around 50 Bq/m3 and the radon risk factor in this region is therefore not particularly significant.

Single-needle celiac plexus block: is needle tip position critical in patients with no regional anatomic distortions?

BACKGROUND: The "single-needle" celiac plexus block is becoming a popular technique. Despite different approaches and methods used to place the needle, the success of the block depends on adequate spread of the injectate in the celiac area. In the present retrospective study, the influence of needle tip position in relation to the celiac artery on injectate spread was evaluated. METHODS: Among 138 cancer patients subjected, via an anterior approach, to computed tomography (CT)-guided single-needle neurolytic celiac plexus block, a radiologist, blinded to the aim of the study, retrospectively selected 53 cases with normal anatomy of the celiac area as judged by CT. The decision was based on images obtained before the block. Patients were then classified into either group A (29 patients), in whom the needle tip was caudad to the celiac artery, and group B (24 patients), in whom it was cephalad. To evaluate CT patterns of neurolytic (mixed with contrast) spread, the celiac area was divided on the frontal plane into four quadrants: upper right and left and lower right and left, as related to the celiac artery. Patient assessments by visual analog scale were reviewed to evaluate the degree of pain relief. Pain relief 30 days after block was judged as long-lasting. The patterns of contrast spread in relation to the needle position and pain relief according to the number of quadrants with contrast were analyzed. RESULTS: The percentage of cases with four quadrants with contrast was higher when the needle tip was cephalad (58%, group B) than when it was caudad (14%, group A) to the celiac artery (P < 0.01). The percentage of patients with four and three quadrants with contrast was also higher in group B at 79% than in group A at 38% (P < 0.01). A significant difference in long-lasting pain relief was observed between patients with four quadrants with contrast (18 of 18, 100%; 95% confidence interval [CI], 81-100%) and patients with three quadrants with contrast (5 of 12, 42%; 95% CI, 15-72%) (P < 0.01). No patients showing two or one quadrant with contrast had long-lasting pain relief. CONCLUSIONS: These findings suggest that, when the celiac area is free from anatomic distortions, and the single-needle neurolytic celiac plexus block technique is used, the needle tip should be positioned cephalad to the celiac artery to achieve a wider neurolytic spread. It also appears that only a complete (four quadrants) neurolytic spread in the celiac area can guarantee long-lasting analgesia.

Giant spinal cord ependymoma in a child. Case report.

Ependymomas of the spinal cord extending to more than ten vertebral segments are rare. A case of a 14-month-old child is described and the other 13 reported cases are reviewed. The finding of a very extensive tumor (from T5 to L5) after only 14 months of life suggests that in our case the tumor was present since birth. Magnetic resonance well shows the real extent of the tumor in height and its different components. Complete removal is often possible even in very extensive ependymomas and results in clinical improvement. Postoperative radiotherapy is necessary only for incompletely removed or malignant ependymomas.

Percutaneous longitudinal tenotomy in chronic Achilles tendonitis.

In the period from August 1989 through December 1992, 42 track and field athletes with unilateral Achilles tendonitis and/or peritendinitis were operated using multiple percutaneous longitudinal tenotomy under local anesthesia following failure of conservative treatment. Patients were reviewed in a special clinic over three consecutive days at an average of 19.2 (9.4) months from the operation. Of the 42 patients operated, 36 (86%) attended. On this occasion, only subjective assessment was carried out. Of the other six patients, four were interviewed by telephone using the same questionnaire; two were lost to follow-up. The results in 25 patients (59.5) were rated as excellent, 11 (28.2%) as good, 4 (9.5%) as fair, and 2 (4.8%) as poor.