Robot-assisted nephroureterectomy for upper tract urothelial carcinoma-feasibility and complications: a single center experience.

BACKGROUND: Robot-assisted nephroureterectomy (RANU) is the primary treatment for upper tract urothelial carcinoma (UTUC) at our hospital for patients with clinical stage less than T2, and for patients with invasive tumours, but unfit for major surgery. OBJECTIVE: To assess peri-operative conditions and outcomes of RANU at our unit, and to evaluate the safety of the procedure. METHODS: The medical records of all 166 patients undergoing RANU for suspected UTUC and followed for more than three months in a large university hospital in Sweden were reviewed retrospectively. After the exclusion of twenty patients because of previous cystectomy, simultaneous surgical procedure, or other tumour types than UTUC in the pathological report, 146 patients remained for the analyses. The primary endpoint was complication rate according to Clavien-Dindo at 90 days. Secondary endpoints were perioperative bleeding, violation of oncological surgical principles, hospital stay, and re-admission within 90 days. RESULTS: The median age was 75 [(Inter Quartile Range) IQR 70-80] years and 57% of the patients had an ASA score above 2. According to Clavien-Dindo, one patient had a grade 3 complication, and no patient had a grade 4-5 complication. The median blood loss was 50 (IQR 20-100) ml and the median hospital stay was 6 (IQR 5-7) days. Twelve patients were re-admitted to the hospital within 90 days (eight with urinary tract infection/haematuria, one with hematoma, and three with other diseases). CONCLUSION: Robot-assisted nephroureterectomy is a safe procedure for patients with upper tract urothelial carcinoma, with a low risk of major surgical complications.

Urostomal ileal conduit complications in association with abdominal wall mesh implantation.

OBJECTIVE: Parastomal hernia (PH) in association with an ileal conduit is a common complication that is difficult to treat. Mesh reinforcement has been suggested to improve outcomes; either as prophylaxis or for treatment of a parastomal hernia during abdominal wall reconstruction. PATIENTS AND METHODS: A retrospective study was performed in consecutive patients subjected to mesh implantation between 2000 and 2016 having a concurrent or previous ileal conduit reconstruction. Postoperative and late urostomal complications, as well as hernia occurrence, were ascertained by a chart review of patients' records. RESULTS: A total of 25 patients were included of whom 13 (52%) developed either a urostomal complication, a PH, or both. Complications were caused by mesh erosion in four patients, of which three were diagnosed more than five years after surgery. Four patients developed a urostomal stenosis. One out of eight patients with urostomal complications were subjected to a new ileal conduit reconstruction and another four to other types of revisional surgery. CONCLUSIONS: Every second patient with an ileal conduit developed either a local urostomal complication, a PH, or both after abdominal wall mesh reconstruction. A careful and cautious attitude towards the use of mesh in patients with an ileal conduit is suggested.

Electrochemotherapy - possible benefits and limitations to its use in the head and neck region.

CONCLUSION: Electrochemotherapy (ECT) is an efficacious treatment. It should, however, be used with some caution in the treatment of head and neck cancer. OBJECTIVES: To assess local tumor control, safety, survival, and functional outcome after treatment of cancer in the head and neck region with ECT. METHODS: Four patients with primary T2 cancer of the oral cavity or oropharynx and one patient with a metastasis of renal cancer in the masseter muscle were treated with ECT with intratumorally administered bleomycin. Control biopsies were carried out 2 months after treatment. Postoperative radiotherapy was performed based on tumor T-stage and the depth of tumor infiltration. Serious adverse events and treatment malfunctions were recorded. The follow-up time was 24 months for the surviving patients and 20 months overall. The PSS-HN scale was used to assess the functional outcome. RESULTS: No local recurrence was recorded in any patient during the follow-up. However, only one patient was treated with ECT alone. There were four serious adverse events: one nearly lethal bleeding, two cases of osteoradionecrosis, and a fistula. One patient died from distant metastasis. The other patients were tumor-free both locally and overall at 24 months. The median functional outcome in all parameters was worse 1 year after treatment.

Electroporation therapy for T1 and T2 oral tongue cancer.

CONCLUSION: Electroporation therapy appears to be a safe treatment achieving excellent local tumor control and very good functional results in our study and it should be further clinically evaluated. OBJECTIVES: The objectives of this study were to assess local tumor control, survival, and effects on speech and eating after treatment of tongue cancer with electroporation therapy, a new local therapeutic modality. In this approach intracellular accumulation of a chemotherapeutic agent is achieved by using a locally applied electrical field. METHODS: Fifteen patients with primary T1 and T2 oral tongue cancer were treated with electroporation therapy with intratumorally administered bleomycin. Postoperative radiotherapy was performed when the tumor infiltration was 5 mm or more. The follow-up time was 24 months for the surviving patients and 20.4 months overall. The effects on eating and speech were assessed using the PSS-HN scale and voice recordings. RESULTS: No local recurrence was recorded in any patient during the follow-up. Three patients died, two from progressive regional disease. Of the 12 surviving patients, 2 patients had regional recurrence and 10 patients including the 5 patients treated with EPT alone were tumor-free both locally and regionally at the last follow-up. The functional outcome for speech and eating were very good.

Adjuvant radiotherapy of women with breast cancer - information, support and side-effects.

UNLABELLED: The aim of this study was to 1) examine the occurrence and burden of side effects over time in the period after post surgical adjuvant radiotherapy in women with breast cancer and 2) explore the women's experiences of given information and need of support to handle side effects. MATERIAL AND METHOD: 171 women with breast cancer receiving post-surgical adjuvant radiotherapy completed a questionnaire on radiotherapy-related side effects (Treatment Toxicity Assessment Tool OTTAT) at four times between the start of radiotherapy and six months after completion. Comparisons were made between women with breast conservative surgery (group A) and women with modified mastectomy (group B), and for having chemotherapy or not (C+ and C-). Questions regarding the experience of delivered information and support were added. RESULTS: Fatigue was the single most prevalent side effect and, together with skin reactions and pain, it also had the highest mean score over the study period and the largest score increase during treatment. The largest increase during the six months was seen for skin reaction, pain, and dyspnoea. The average score for skin reaction was significantly higher in group B than in group A. A majority of the women experienced the given information and support as satisfying and a need for follow-up of the side-effects was expressed. CONCLUSION: Nursing for women with breast cancer receiving adjuvant radiotherapy should focus on preventing and treating side effects, and also include the period post treatment. There is a need for developing evidence based guidelines including guidelines for follow-up.

Novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia and multisystem failure.

A Saudi Arabian family presented with adult onset autosomal dominant progressive external ophthalmoplegia (adPEO) complicated by late onset reversible failure of the CNS, respiratory, hepatic, and endocrine systems. Clinical findings were suggestive of mitochondrial dysfunction and multiple mitochondrial DNA deletions were demonstrated on long range and real time polymerase chain reaction assays but not on Southern blotting. The disorder is caused by a novel heterozygous PEO1 mutation predicting a Leu360Gly substitution in the twinkle protein. The peculiar clinical presentation expands the variable phenotype observed in adPEO and Twinkle gene mutations.

Gene dosage imbalances in patients with 46,XY gonadal DSD detected by an in-house-designed synthetic probe set for multiplex ligation-dependent probe amplification analysis.

The development of a testis requires the proper spatiotemporal expression of the SRY gene and other genes that act in a dosage-sensitive manner. Mutations in the SRY gene account for only 10-15% of patients with 46,XY gonadal disorder of sex development (DSD). To enable the diagnostics of deletions and duplications of genes known to be involved in different forms of DSD, we developed a synthetic probe set for multiplex ligation-dependent probe amplification (MLPA) analysis. Here, we report the results from the analysis of 22 patients with 46,XY gonadal DSD. The analysis with the DSD probe set has led to the identification of two copy number variations, an 800-kb NR0B1 (DAX1) locus duplication on Xp21 in a patient with isolated partial gonadal dysgenesis and a duplication of the SRD5A2 gene that represents a rare normal variant. The described MLPA kit represents an optimal complement to DNA sequence analysis in patients with DSD, enabling screening for deletions and duplications of several genes simultaneously. Furthermore, the second identification of an NR0B1 locus duplication in a patient with isolated gonadal dysgenesis, without dysmorphic features and/or mental retardation, highlights the importance of evaluating NR0B1 duplication in patients with gonadal dysgenesis.

Charcot-Marie-Tooth disease: a clinico-genetic confrontation.

Charcot-Marie-Tooth disease (CMT) is the most common neuromuscular disorder. It represents a group of clinically and genetically heterogeneous inherited neuropathies. Here, we review the results of molecular genetic investigations and the clinical and neurophysiological features of the different CMT subtypes. The products of genes associated with CMT phenotypes are important for the neuronal structure maintenance, axonal transport, nerve signal transduction and functions related to the cellular integrity. Identifying the molecular basis of CMT and studying the relevant genes and their functions is important to understand the pathophysiological mechanisms of these neurodegenerative disorders, and the processes involved in the normal development and function of the peripheral nervous system. The results of molecular genetic investigations have impact on the appropriate diagnosis, genetic counselling and possible new therapeutic options for CMT patients.

Spastin gene mutations in Bulgarian patients with hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is an extremely heterogeneous group of neurodegenerative disorders affecting the longest axons in the central nervous system. The most common genetic form accounting for about 40% of the autosomal-dominant HSP (ADHSP) cases is spastin gene, SPG4. We performed mutation screening of the spastin gene on 36 unrelated HSP patients from three different ethnic groups (Bulgarian, Turks and Gypsies) and found four new mutations and one already reported. The phenotype-genotype correlations in Bulgarian SPG4 patients showed a great difference in the age at disease onset between patients with missense mutations and those harboring deletions and splice-site mutations. Our study is the first to present corroborative clinical data in favor of the general hypothesis that the clinical course of the disease is related to the type of the spastin mutation. The clinical and genealogical findings in Bulgarian SPG4 patients suggest that a positive family history for inheritance as an autosomal-dominant trait is a strong indication for spastin mutation screening.

POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement.

OBJECTIVE: To identify POLG mutations in patients with sensory ataxia and CNS features. METHODS: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European families. The authors conducted sequencing of coding exons of POLG, C10orf2 (Twinkle), and ANT1 and analyzed muscle mitochondrial DNA (mtDNA), including Southern blot analysis and long-range PCR. RESULTS: Ataxia occurred in combination with various CNS features, including myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions on MRI, and neuronal loss in discrete gray nuclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate-induced hepatotoxicity occurred less frequently. Two patients died without preceding signs of progressive external ophthalmoplegia. In muscle, typical findings of mitochondrial disease, such as ragged red fibers and Southern blot mtDNA abnormalities, were absent. POLG mutations were present in eight patients, including two isolated cases, and one Finnish and two unrelated Belgian families contained in total six patients. All POLG mutations were recessive, occurring in a homozygous state in seven patients and in a compound heterozygous state in one patient. The novel W748S mutation was identified in five patients from three unrelated families. CONCLUSIONS: The clinical spectrum of recessive POLG mutations is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, myopathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondrial DNA also are not mandatory features associated with POLG mutations.

Symmetry of two-terminal nonlinear electric conduction.

The well-established symmetry relations for linear transport phenomena cannot, in general, be applied in the nonlinear regime. Here we propose a set of symmetry relations with respect to bias voltage and magnetic field for the nonlinear conductance of two-terminal electric conductors. We experimentally confirm these relations using phase-coherent, semiconductor quantum dots.

Patient homozygous for a recessive POLG mutation presents with features of MERRF.

Both dominant and recessive missense mutations were recently reported in the gene encoding the mitochondrial DNA polymerase gamma (POLG) in patients with progressive external ophthalmoplegia (PEO). The authors report on a patient homozygous for a recessive missense mutation in POLG who presented with a multisystem disorder without PEO. The most prominent features were myoclonus, seizure, and sensory ataxic neuropathy, so the clinical picture overlapped with the syndrome of myoclonus, epilepsy, and ragged red fibers (MERRF).

Charcot-Marie-Tooth disease with giant axons: a clinicopathological and genetic entity.

The authors report an Italian family with autosomal-dominant Charcot-Marie-Tooth disease (CMT) in which there were giant axons in the sural nerve biopsy. Linkage to the known CMT2 loci (CMT2A, CMT2B, CMT2D, CMT2F) and mutations in the known CMT2 genes (Cx32, MPZ, NEFL), GAN, NEFM, and CMT1A duplication/HNPP deletion were excluded. This family with CMT and giant axons has a pathologic and genetic entity distinct from classic CMT.

A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy.

Generalized epilepsy with febrile seizures plus (GEFS+) is a clinically and genetically heterogeneous syndrome with childhood onset, characterized by febrile seizures (FS) and a variety of afebrile epileptic seizure types. The authors performed a mutational analysis of SCN1B on 74 unrelated probands with GEFS+, FS, or FS plus (FS+). In a family with FS+ and early-onset absence epilepsy, a mutation was identified that predicts a deletion of five amino acids in the extracellular immunoglobulin-like domain of SCN1B and potential loss of function. SCN1B mutations are associated with GEFS+ and may have a role in the elicitation of absence seizures.

Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia.

Autosomal recessive progressive external ophthalmoplegia is a mitochondrial disease characterized by accumulation of multiple large-scale deletions of mitochondrial DNA. We previously reported missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma in two nuclear families compatible with autosomal recessive progressive external ophthalmoplegia. Here, we report a novel POLG missense mutation (R627W) in a sporadic patient and we provide genetic support that all these POLG mutations are actually causal and recessive. The novel patient presented with sensory ataxic neuropathy and has the clinical triad of sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO). This is the first finding of a genetic cause of Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis and it implies that this disorder may actually be a variant of autosomal recessive progressive external ophthalmoplegia. Sensory neuropathy is the initial feature in Belgian compound heterozygote autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation, which occurs at a frequency of 0.6% in the Belgian population.

[Hereditary neuropathy with liability to pressure palsies: study of six Spanish families]. / Neuropathies héréditaires sensibles à la pression: étude de six familles espagnoles.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant inherited demyelinating neuropathy typically characterized by recurrent episodes of acute painless peripheral nerve palsies often preceded by minor trauma or compression at entrapment sites. However, less classical phenotypes have been reported. A 1.5 Mb deletion in chromosome 17 p11.2 has been shown to be the genetic basis of the disease in the majority of HNPP patients. The few families without this deletion harbored a mutation in the PMP22 gene. We performed a clinical, neurophysiological and molecular genetic study of 6 Spanish HNPP families. Five families (22 individuals) showed the classical chromosome 17 p11.2 deletion and one family (3 individuals) had a novel 3'splice-site mutation in PMP22. Neurophysiological abnormalities were detected in all symptomatic (n=21) and asymptomatic (n=4) deletion or mutation carriers, even in childhood. In addition to the typical presentation we observed other phenotypes: recurrent focal short-term sensory symptoms, a progressive mononeuropathy, a Charcot-Marie-Tooth (CMT) disease-like chronic progressive polyneuropathy, a chronic sensory polyneuropathy and a chronic inflammatory demyelinating polyneuropathy. We report new or very rare phenotypesThese atypical clinical aspects and intrafamilial heterogeneity are present in families with the HNPP deletion as well as in the family with the PMP22 mutation. However, the CMT disease-like chronic polyneuropathy was more common in the PMP22 mutation family. Intrafamilial heterogeneity also seemed to be more pronounced in this kinship. Patients in this family had a mild chronic motor and sensory polyneuropathy neurophysiologically characterized by delayed distal latencies, reduced nerve conduction velocities (NCV) within the demyelinating range, mildly decreased amplitudes of motor and sensory evoked potentials and absence of conduction blocks. In contrast, patients with the common HNPP deletion, regardless of their phenotype, had a diffuse increase in distal motor latencies contrasting with moderately reduced motor NCVs, preserved sensory nerve action potentials, slowing of NCVs at the common entrapment sites and occasionally conduction blocks. In this study we confirm the clinical and molecular heterogeneity of HNPP, emphasizing the need for a mutation analysis of the PMP22 gene when the common 17p11.2 deletion is not found in clinically suspected HNPP patients. We conclude that the 3'splice-site mutation in PMP22 and the common HNPP deletion have largely the same functional consequences although some clinical and neurophysiological differences were observed.

Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation.

The dense-cored plaques are considered the pathogenic type of amyloid deposition in Alzheimer's disease brains because of their predominant association with dystrophic neurites. Nevertheless, in > 90% of cases of Alzheimer's disease amyloid is also deposited in cerebral blood vessel walls (congophilic amyloid angiopathy; CAA) but its role in Alzheimer's disease pathogenesis remains enigmatic. Here, we report a family (family GB) in which early-onset Alzheimer's disease was caused by a novel presenilin 1 mutation (L282V). This was unusually severe CAA reminiscent of the Flemish amyloid precursor protein (A692G) mutation we reported previously, which causes Alzheimer's disease and/or cerebral haemorrhages. In family GB, however, the disease presented as typical progressive Alzheimer's disease in the absence of strokes or stroke-like episodes. Similarly, neuroimaging studies and neuropathological examination favoured a degenerative over a vascular dementia. Interestingly, an immunohistochemical study revealed that, similar to causing dense-cored amyloid plaques, CAA also appeared capable of instigating a strong local dystrophic and inflammatory reaction. This was suggested by the observed neuronal loss, the presence of tau- and ubiquitin-positive neurites, micro- and astrogliosis, and complement activation. Together, these data suggest that, like the dense-cored neuritic plaques, CAA might represent a pathogenic lesion that contributes significantly to the progressive neurodegeneration that occurs in Alzheimer's disease.

Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions.

Progressive external ophthalmoplegias (PEO) characterized by accumulation of large-scale mitochondrial DNA (mtDNA) deletions are rare human diseases. We mapped a new locus for dominant PEO at 15q22-q26 in a Belgian pedigree and identified a heterozygous mutation (Y955C) in the polymerase motif B of the mtDNA polymerase gamma (POLG). We identified three additional POLG missense mutations compatible with recessive PEO In two nuclear families. POLG is the only DNA polymerase responsible for mtDNA replication.

A comparison of quadruple semitendinosus and patellar tendon grafts in reconstruction of the anterior cruciate ligament.

In a two-centre study, 164 patients with unilateral instability of the anterior cruciate ligament were prospectively randomised to arthroscopic reconstruction with either a patellar tendon graft using interference screw fixation or a quadruple semitendinosus graft using an endobutton fixation technique. The same postoperative rehabilitation protocol was used for all patients and follow-up at a median of 31 months (24 to 59) was carried out by independent observers. Four patients (2%) were lost to follow-up. No significant differences were found between the groups regarding the Stryker laxity test, one-leg hop test, Tegner activity level, Lysholm score, patellofemoral pain score, International Knee Documentation Committee (IKDC) score or visual analogue scale, reflecting patient satisfaction and knee function. Slightly decreased extension, compared with the non-operated side, was found in the patellar tendon group (p < 0.05). Patients with associated meniscal injuries had lower IKDC, visual analogue (p < 0.01) and Lysholm scores (p < 0.05) than those without such injuries. Patients in whom reconstruction had been carried out less than five months after the injury had better final IKDC scores than the more chronic cases (p < 0.05). We conclude that patellar tendon and quadruple semitendinous tendon grafts have similar outcomes in the medium term. Associated meniscal pathology significantly affects the final outcome and early reconstruction seems to be beneficial.

A novel 3'-splice site mutation in peripheral myelin protein 22 causing hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant, demyelinating peripheral neuropathy. Clinical hallmarks are recurrent painless focal neuropathies mostly preceded by minor trauma or compression at entrapment sites of peripheral nerves. In the majority of the patients, HNPP is caused by a 1.5 Mb deletion on chromosome 17p11.2-p12 containing the peripheral myelin protein 22 (PMP22) gene. Point mutations within this gene are reported in only a few families. We report a novel mutation in the PMP22 gene in a Spanish family with HNPP. The mutation is a 3' splice-site mutation, preceding coding exon 3 (c.179-1 G>C), causing a mild HNPP phenotype.