Search

Antibody-drug conjugates (ADCs) deliver effective medications to tumor cells that express specific antigens, maximizing efficacy and reducing adverse effects. Because ado-trastuzumab emtansine was approved in 2013, 5 ADCs received US Food and Drug Administration approval for solid tumor treatment. Technical advancements in the development of each component of ADCs allowed novel monoclonal antibodies, linkers, and payloads to increase drug transport to malignant cells and drug activity even in cancers with heterogeneous antigen expression. In addition, several ADCs are in development using new molecular targets expressed across a broad range of histologies to allow the use of ADC biomarker–driven therapy irrespective of the primary tumor site. This suggests that the future efficacy of ADCs in multiple histologies may be similar to other classes of drugs that are considered histology-agnostic therapies nowadays. This review focuses on novel ADCs for the treatment of solid tumors, including topics such as their structure and mechanism of action, the latest indications of already US Food and Drug Administration–approved ADCs, and the outlook for new promising ADCs under development for the treatment of tumors of various histologies.

Objectives: To study the patterns of vitreous incarceration in sutured vs non-sutured sclerotomies in patients subjected to 25-gauge macular surgery. Methods: A prospective study of 135 eyes affected by epiretinal membrane or macular hole. Vitreal disposition was evaluated via ultrasound biomicroscopy (UBM) at the sclerotomy sites between 30 and 40 days after surgery, once the tamponade had completely disappeared. Results: In total, 349 sclerotomies (86.2%) of 99 patients were non-sutured while 56 sclerotomies (13.8%) of 36 patients were sutured at the end of the surgical procedure. Among the 36 patients with sutured sclerotomies, 15 out of 36 (41.6%) had at least two sclerotomies sutured. All the sclerotomy sites were evaluated (405 sclerotomies). Sclerotomy suture was significantly associated with a less aggressive pattern of vitreal incarceration (OR: 0.16, 95% CI: 0.07–0.35, p< 0.001). Compared to preoperative values, day 1 post operative IOP was not significantly different in patients with sutured sclerotomies, while patients with non-sutured sclerotomies had a significantly lower day 1 post operative IOP. Conclusions: In 25-gauge macular surgery, UBM evaluation documented a higher rate of postoperative vitreous incarceration in the non-sutured sclerotomies, confirming the previously postulated role of the residual vitreous, left at the end of the surgery, in closing the sclerotomy site.

We identified three non-related patients manifesting a childhood-onset progressive neuromyopathy with congenital cataracts, delayed walking, distal weakness and wasting, glaucoma and swallowing difficulties. Electrophysiology and nerve biopsies showed a mixed axonal and demyelinating neuropathy, while muscle biopsy disclosed both neurogenic and myopathic changes with ragged red fibers, and muscle MRI showed consistent features across patients, with a peculiar concentric disto-proximal gradient of fatty replacement. We used targeted next generation sequencing and candidate gene approach to study these families. Compound biallelic heterozygous variants, p.[(Pro648Arg)]; [(His932Tyr)] and p.[(Thr251Ile),(Pro587Leu)]; [(Arg943Cys)], were found in the three patients causing this homogeneous phenotype. Our report on a subset of unrelated patients, that showed a distinct autosomal recessive childhood-onset neuromyopathy with congenital cataracts and glaucoma, expands the clinical spectrum of POLG-related disorders. It also confirms the association between cataracts and neuropathy with variants in POLG. Early onset cataract is otherwise rare in POLG-related disorders and so far reported only in a few patients with the clinical pattern of distal myopathy or neuromyopathy.

Ultrasound biomicroscopy showed no significant differences in perisclerotomy vitreous incarceration patterns between valved and nonvalved 23- and 25-gauge macular surgeries. In addition, no difference in vitreous patterns was present between valved 23, 25, and 27 gauges.

Purpose: We describe a technique to avoid decentration of the visual axis of the Boston type 1 keratoprosthesis (Kpro), performing 2 concentric trephinations with femtosecond laser.Methods: Two concentric side cuts were performed in a donor cornea using the 150-kHz Intralase™ FS laser. Within the same applanation procedure, an 8.5-mm-diameter anterior side cut was performed, followed by a concentric 3-mm-diameter anterior side cut.Results: The technique was successfully replicated in 7 cases.Conclusions: Femtosecond laser-assisted double trephination results in a correctly prepared donor cornea, and in an inner side precisely matched with the prosthesis. At the end of the surgery, the Kpro was correctly centered.

Purpose To determine the microbial contamination of the irrigating fluids at the time of phacoemulsification after the use of topical povidone-iodine and antibiotics prophylaxis.Methods A total of 119 patients undergoing cataract surgery were enrolled in this prospective study. All patients received 5 mg/mL levofloxacin starting from the day prior to surgery and topical and 5% povidone-iodine drops starting from 30 minutes before the surgery. At the end of each surgery, 2 samples of drainage liquids were sterilely collected from the drainage bags (DBL) and from the peristaltic pump single-cassettes (PCL) of the phacoemulsification machine. Search for aerobic and anaerobic bacteria and fungi was performed.Results Seventy-five patients (31.5%) revealed a growth of at least one microbial species (53 DBL and 22 PCL, 44.5% vs 18.5%; p<0.001). Sixty-six patients (55.5%) had at least one positive intraoperative solution. Overall, 111 microbial strains were collected: 82 (74%) Gram-positive bacteria, 20 (18%) fungi, and 9 (8%) Gram-negative bacteria. Thirteen staphylococcal isolates from PCL, compared with 52 out of DBL (11% vs 43.7%, p<0.001), fungi were essentially isolated from PCL. No significant correlation was found between microbial isolation and risk factors. No postsurgical infective complication occurred in the follow-up.Conclusions Evaluation of intraoperative fluids can provide evidence on sources or vehicles of postsurgical infections. Antibiotic prophylaxis and topical povidone-iodine can significantly contribute to minimize the risk of endophthalmitis.

Background.Periodic lateralised epileptiform discharges (PLEDs) are EEG patterns consisting of periodic or pseudoperiodic unilateral, focal or hemispheric epileptiform discharges at a rate of 1‐2 Hz. PLEDs may be triggered by acute brain injuries or systemic metabolic changes such as fever, hyperglycaemia or electrolyte imbalance and may result in disturbance of consciousness and/or neurological deficits. Case report.A 58‐year‐old female with a history of focal epilepsy and deep brain haematoma presented with acute change in awareness, associated with EEG evidence of PLEDs, three days after a left internal carotid artery stenting procedure. Clinical examination, laboratory testing and MRI were unchanged with respect to pre‐stenting investigations. Conclusion.In this patient, PLEDs may have been triggered by local haemodynamic changes due to reperfusion after stenting in a previously damaged brain area.

Periodic lateralised epileptiform discharges (PLEDs) are EEG patterns consisting of periodic or pseudoperiodic unilateral, focal or hemispheric epileptiform discharges at a rate of 1–2 Hz. PLEDs may be triggered by acute brain injuries or systemic metabolic changes such as fever, hyperglycaemia or electrolyte imbalance and may result in disturbance of consciousness and/or neurological deficits. A 58-year-old female with a history of focal epilepsy and deep brain haematoma presented with acute change in awareness, associated with EEG evidence of PLEDs, three days after a left internal carotid artery stenting procedure. Clinical examination, laboratory testing and MRI were unchanged with respect to pre-stenting investigations. In this patient, PLEDs may have been triggered by local haemodynamic changes due to reperfusion after stenting in a previously damaged brain area.

Femtosecond laser sculpturing of corneal tissue is commonly used for the preparation of endothelial flaps. Diode laser welding of ocular tissues is a procedure that enables minimally invasive suturing of tissues. The combination of these laser based techniques results in a new approach to minimally invasive ophthalmic surgery, such as in endothelial corneal transplant (or endothelial keratoplasty - EK). In this work we present the "all laser" EK performed in human subjects. 24 pseudophakic patients with bullous keratopathy underwent EK: the femtosecond laser was used to prepare the 100 ìm thick and 8.5 mm diameter donor Descemet endothelial flap. After staining the stromal layer of the donor flap with a liquid ICG solution, the donor flap was inserted in the recipient eye by the use of the Busin injector. Then, the endothelial layer was laser-welded to the recipient eye (10 laser spots around the periphery of the flap), in order to reduce the risk of postoperative dislocation of the transplanted flap. A transplanted flap engraftment was observed in all the treated eyes. The staining procedure used to perform laser welding also enabled to evidence the stromal side of the donor flap, so as the flap was always placed in the right side position. The endothelial cells counts in both the laserwelded flaps and in a control group were in good agreement. The proposed technique is easy to perform and enables the reduction of postoperative endothelial flap dislocations.

Purpose To evaluate the long-term results of air-guided manual deep anterior lamellar keratoplasty (DALK) and to perform confocal microscopy on postoperative DALK corneas.Methods Seven postoperative consecutive DALK corneas were evaluated 1 year after suture removal. All patients underwent a complete ophthalmologic examination evaluating visual acuity, astigmatism, corneal thickness, and endothelial cell count. Confocal microscopy was performed to examine the corneas of the seven eyes and to obtain the measured interface depth.Results Eighteen months after surgery, the mean postoperative uncorrected visual acuity was 20/38 and the mean best-corrected visual acuity was 20/23. Postoperative mean value of residual recipient stroma thickness was 65.57 μm ± 28.74.Conclusions Maximum depth DALK can lead to significant advantages for quality of vision when compared to other types of anterior lamellar keratoplasty. Still, it remains a challenging procedure. These results show that a deep dissection without baring Descemet membrane makes good visual results possible, preventing corneal perforation and conversion to penetrating graft.

We report a 30-year-old woman with hypertelorism, ptosis, and myopia associated with drug-resistant epilepsy (DRE, Lennox–Gastaut syndrome), mental delay, growth deficiency, ectodermal defects, and osteopenia. To the best of our knowledge, this patient has an unusual combination of symptoms not previously described, associated with severe central nervous system dysfunction. The ectodermal defects were present in a very intriguing form, were difficult to diagnose, and did not conform to any classification or previous description. © 2004 Wiley-Liss, Inc.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset familial disease with prominent myelinated fibers in the optic fundus. ARSACS is frequent in the Charlevoix-Saguenay region of Quebec but rare elsewhere. Mutations in SACS, encoding sacsin, a protein of unknown function, are associated with ARSACS. The authors identified three new SACSmutations in two Italian patients whose phenotype closely matches that of Quebec cases, but without retinal striation.

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder of early onset, clinically characterized by a progressive involvement of both peripheral and CNS. The diagnosis is based on the presence of characteristic giant axons, filled with neurofilaments, on nerve biopsy. Recently, the defective protein, gigaxonin, has been identified and different pathogenic mutations in the gigaxonin gene have been reported as the underlying genetic defect. Gigaxonin, a member of the BTB/kelch superfamily proteins, seems to play a crucial role in the cross talk between the intermediate filaments and the membrane network. The authors report clinical and molecular findings in five Italian patients with GAN. This study shows the allelic heterogeneity of GAN and expands the spectrum of mutations in the GANgene. The frequent occurrence of private mutations stresses the importance of a complete gene analysis.

Nerve growth factor (NGF) is a neurotrophin that is expressed during muscle development and is also capable of favoring muscle regeneration in experimental studies. The presence of NGF in muscular dystrophies, such as Duchenne and Becker muscular dystrophies, has never been fully explored. By means of immunohistochemistry, we show that regenerating muscle fibers from such patients consistently express NGF, as do myofibroblasts and mast cells. By contrast, rest fibers from dystrophic patients, as well as muscle fibers from healthy, control patients and even regenerative muscle fibers in polymyositis do not show NGF immunoreactivity. The paracrine effect of NGF on muscle regeneration, as well as its chemoattractant capacities for mast cells, may contribute to explaining why regenerating fibers most frequently occur in clusters and why mast cells are more numerous in dystrophic muscles. Moreover, being a mediator of wound healing and tissue fibrosis, NGF may contribute to long-term muscle regeneration impairment by tissue fibrosis in the muscular dystrophies. Muscle Nerve 27: 370–373, 2003

Nerve growth factor (NGF) is a neurotrophin that is expressed during muscle development and is also capable of favoring muscle regeneration in experimental studies. The presence of NGF in muscular dystrophies, such as Duchenne and Becker muscular dystrophies, has never been fully explored. By means of immunohistochemistry, we show that regenerating muscle fibers from such patients consistently express NGF, as do myofibroblasts and mast cells. By contrast, rest fibers from dystrophic patients, as well as muscle fibers from healthy, control patients and even regenerative muscle fibers in polymyositis do not show NGF immunoreactivity. The paracrine effect of NGF on muscle regeneration, as well as its chemoattractant capacities for mast cells, may contribute to explaining why regenerating fibers most frequently occur in clusters and why mast cells are more numerous in dystrophic muscles. Moreover, being a mediator of wound healing and tissue fibrosis, NGF may contribute to long‐term muscle regeneration impairment by tissue fibrosis in the muscular dystrophies. Muscle Nerve 27: 370–373, 2003

No abstract

No abstract

Three siblings with genetically assessed cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with core-like lesions and mitochondrial abnormalities in muscles are described. Involvement of the Ryanodine receptor 1 gene was excluded. In the current cases, the relation between molecular genetic lesion and muscle fiber abnormalities remains to be determined, but the Notch3gene may influence mitochondrial metabolism.

McLeod syndrome is caused by mutations of XK, an X‐chromosomal gene of unknown function. Originally defined as a peculiar Kell blood group variant, the disease affects multiple organs, including the nervous system, but is certainly underdiagnosed. We analyzed the mutations and clinical findings of 22 affected men, aged 27 to 72 years. Fifteen different XKmutations were found, nine of which were novel, including the one of the eponymous case McLeod. Their common result is predicted absence or truncation of the XK protein. All patients showed elevated levels of muscle creatine phosphokinase, but clinical myopathy was less common. A peripheral neuropathy with areflexia was found in all but 2 patients. The central nervous system was affected in 15 patients, as obvious from the occurrence of seizures, cognitive impairment, psychopathology, and choreatic movements. Neuroimaging emphasized the particular involvement of the basal ganglia, which was also detected in 1 asymptomatic young patient. Most features develop with age, mainly after the fourth decade. The resemblance of McLeod syndrome with Huntington's disease and with autosomal recessive chorea‐acanthocytosis suggests that the corresponding proteins—XK, huntingtin, and chorein—might belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia.

The authors identified a novel mtDNA mutation (T9176G) in the ATPase 6 gene in a family in which a 10-year-old girl had a severe neurodegenerative disorder, her elder sister had died of Leigh syndrome (LS), and a maternal uncle had a spinocerebellar disorder. Biochemical studies disclosed a reduced rate of ATP synthesis in skin fibroblast cultures from the proposita as the likely explanation of her severe illness. The findings expand the genetic variants associated with LS.

We recently described a novel contiguous gene deletion syndrome (AMME) in Xq22.3 that includes Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E). While the Alport syndrome is due to deletion of the COL4A5 gene, no other genes are known in the region with the exception of our recent finding of the FACL4 gene. In our effort to isolate additional genes from the deleted region, we have identified the gene named AMMECR1 (Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis chromosomal region gene 1). RACE experiments and screening of cDNA libraries enabled us to obtain the entire ORF of the gene (1002 bp) followed by about 2 kb of 3′UTR. AMMECR1 is composed of six exons, shows a ubiquitous 6.5-kb transcript, and codes for a protein with a molecular mass of 35.5 kDa. Sequence analysis revealed that this gene is conserved in several species ranging fromCaenorhabditis elegansand yeast to micro-organisms. Exon 2 of AMMECR1 encodes a domain consisting of six amino acids identically conserved throughout the course of evolution and whose function is as yet unknown. Analysis of the predicted protein product using ExPAsy tools raises the possibility that the gene may code for a regulatory factor potentially involved in the development of AMME contiguous gene deletion syndrome.

Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant muscular disorder associated with a short (&lt;35 kb) EcoRI/BlnI fragment resulting from deletion of an integral number of units of a 3.3-kb repeat located at 4q35. In this study, we determined fragment sizes separated by pulsed-field gel electrophoresis in a patient with an apparently sporadic case of FSHD and in his healthy family members. A 38-kb fragment was detected in the proband, in his older brother, and in their father. This finding prompted a clinical reevaluation of the father and brother. A subclinical phenotype restricted to abdominal muscle weakness was detected, and serum creatine kinase values were found to be elevated in both. The proband's brother also showed evidence of an independently occurring subtelomeric rearrangement of 4q35, which normally occurs in about 20% of the population. The identification of a “borderline” 38-kb EcoRI/BlnI fragment in an affected subject and his very mildly affected relatives extends the size range of disease alleles and expands existing data on the variable intrafamilial expressivity of FSHD. This study highlights the importance of a careful molecular and clinical analysis extended to family members of apparently sporadic cases with larger EcoRI/BlnI fragments for accurate diagnosis and appropriate genetic counseling in FSHD. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 1437–1441, 1999

Abstract: Muscle biopsy tissue from a patient affected by the juvenile form of neuronal ceroid lipofuscinosis (NCL) was studied immunohistochemically using antibodies to β-amyloid peptide and amyloid precursor protein. Positive reaction in muscle was specifically localized to autophagic vacuoles and blood vessel walls. Increased acid phosphatase reaction suggested enhanced lysosomal activity. We hypothesize that β-amyloid is deposited in NCL muscle by a lysosomal mechanism similar to that proposed in other disorders involving β-amyloid.

Facioscapulohumeral dystrophy (FSHD) is an autosomal‐dominant muscular disorder associated with a short (<35 kb) EcoRI/BlnI fragment resulting from deletion of an integral number of units of a 3.3‐kb repeat located at 4q35. In this study, we determined fragment sizes separated by pulsed‐field gel electrophoresis in a patient with an apparently sporadic case of FSHD and in his healthy family members. A 38‐kb fragment was detected in the proband, in his older brother, and in their father. This finding prompted a clinical reevaluation of the father and brother. A subclinical phenotype restricted to abdominal muscle weakness was detected, and serum creatine kinase values were found to be elevated in both. The proband's brother also showed evidence of an independently occurring subtelomeric rearrangement of 4q35, which normally occurs in about 20% of the population. The identification of a “borderline” 38‐kb EcoRI/BlnI fragment in an affected subject and his very mildly affected relatives extends the size range of disease alleles and expands existing data on the variable intrafamilial expressivity of FSHD. This study highlights the importance of a careful molecular and clinical analysis extended to family members of apparently sporadic cases with larger EcoRI/BlnI fragments for accurate diagnosis and appropriate genetic counseling in FSHD. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 1437–1441, 1999

Control of complement deposition on autologous cells is mediated by a group of complement regulatory membrane proteins acting at different levels of the complement cascade. Decay accelerating factor (CD55) prevents the assembly of C3 convertases and CD59 membrane inhibitor of reactive lysis (MIRL) restricts homologous complement lysis by the membrane attack complex of complement (MAC) by inhibition of C5b‐8 catalyzed insertion of C9. The aim of this work was to study the eventual expression of CD55 and CD59 on human skeletal muscle fibers. Highly sensitive immunoblotting using murine monoclonal antibodies showed that CD59, but not CD55, was present in skeletal muscle fibers. Immunocytochemistry with a monoclonal antibody against CD59 demonstrated a dense granular immunostaining mainly localized at the level of the sarcolemma. Thus, CD59, but not CD55, is expressed on normal skeletal muscle fibers. CD59 may play a prominent role in preventing MAC deposition and subsequent complement‐mediated damage in myopathies where the complement system activation is involved. © 1997 John Wiley & Sons, Inc.

From a series of 230 subjects with infantile spasms (I.S.) observed from 1955 to 1982, 191 cases with sufficient data on follow-up and evaluation were selected. The period of follow-up in 100 subjects ranged from 3 months to 3 years and was more than 3 years in the remaining 91 patients. Disappearance of spasms and normal psychomotor development was observed in 34 of the 61 idiopathic and post-infectious cases. In 130 subjects with secondary forms normal psychomotor development was observed in only two patients; disappearance of spasms was noted in 54 and normalisation of the EEG in 13 subjects. Satisfactory long term results can be obtained with a relatively low dose of corticotropin in a considerable number of patients having idiopathic and post-infectious forms of I.S. To obtain the best results treatment should be started as soon as possible.

The cases of two sisters with late infantile Hallervorden-Spatz disease are reported, one of whom has died. Autopsy of the deceased patient showed typical pallidal lesions, such as axonal spheroids and iron deposits, without involvement of the substantia nigra. Ultrastructural examination revealed that pallidal axonal enlargements consisted of collecition of mitochondria, dense bodies, vesicles and amorphous material. In the living patient, brain MRI showed the classical “tiger's eye” appearance of the globus pallidus. Retinitis pigmentosa, acanthocytosis and slight neuromuscular involvement with an increase in serum creatine kinase were observed in both subjects. The appearance of the globus pallidus on MRI was in line with the pathological abnormalities. Ultrastructural differences between the principal disorders characterized by neuroaxonal dystrophy are compared and the clinical spectrum and similarities of the different forms of neuroacanthocytosis analysed.

An immunohistochemical and ultrastructural analysis of dystrophic axons (DAs) in the brain and peripheral nerve of a patient with familial infantile neuroaxonal dystrophy (INAD) and in the brain of a patient with familial Hallervorden-Spatz Disease (HSD) revealed prevalent membrano-tubular or granulo-vesicular profiles with a graded pattern of evolution in INAD, while dense bodies, vesicles and amorphous material were pressent in HSD. DAs immunoreactivity with t-protein and 200 kDa-neurofilament antibodies was stronger in HSD than in INAD. In both cases immunohistochemistry was positive for ubiquitin and negative for ß-tubulin and ß-amyloid. Distinct ultrastructural features and immunoreactivity pattern of cytoskeletal components suggest different pathogenetic mechanisms.

We report a patient who developed a chronic sensory motor polyneuropathy and a progressive myelopathy 4 years after a tick bite. An increased serum antibody titer to Borrelia burgdorferisuggested a diagnosis of Lyme neuroborreliosis, although a concomitant cervical spondylosis probably contributed to spinal cord damage. Treatment with ceftriaxone resulted in a marked improvement of neuropathic symptoms, providing indirect evidence of spirochetal infection. Search for B. burgdorferiDNA by polymerase chain reaction amplification on sural nerve confirmed the diagnosis, demonstrating that the spirochete localized in the peripheral nervous system. The presence of complement membrane attack complex deposits and macrophage infiltrates around epineurial vessels and within the endoneurium suggests that the neuropathy in our patient was immune‐mediated. © 1997 John Wiley & Sons, Inc. Muscle Nerve20:969–975, 1997