HPV-positive clinically advanced squamous cell carcinoma of the urinary bladder (aBSCC): A comprehensive genomic profiling (CGP) study.

BACKGROUND: Advanced bladder squamous cell carcinoma (aBSCC) is an uncommon form of urinary bladder malignancy when compared with the much higher urothelial carcinoma incidence. We studied the genomic alteration (GA) landscape in a series of aBSCC based on the association with human papilloma virus (HPV) to determine if differences in GA would be observed between the positive and negative groups. METHODS: Using a hybrid capture-based FDA-approved CGP assay, a series of 171 aBSCC were sequenced to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. Programmed cell death ligand -1 (PD-L1) expression was determined by IHC (Dako 22C3) with negative expression when PD-L1 was 0, lower expression of positivity set at 1 to 49%, and higher expression set at ≥50% expression. RESULTS: Overall, 11 (6.4%) of the aBSCC were found to harbor HPV sequences (10 HPV16 and 1 HPV 11). HPV+ status was identified slightly more often in women (NS) and in younger patients (P = 0.04); 2 female patients with aBSCC had a prior history of SCC including 1 anal SCC and 1 vaginal SCC. HPV+ aBSCC had fewer GA/tumor (P < 0.0001), more inactivating mutations in RB1 (P = 0.032), and fewer inactivating GA in CDKN2A (P < 0.0001), CDKN2B (P = 0.05), TERT promoter (P = 0.0004) and TP53 (P < 0.0001). GA in genes associated with urothelial carcinoma including FGFR2 and FGFR3 were similar in both HPV+ and HPV- aBSCC groups. MTAP loss (homozygous deletion) which has emerged as a biomarker for PRMT5 inhibitor-based clinical trials was not identified in any of the 11 HPV+ aBSCC cases, which was significantly lower than the 28% positive frequency of MTAP loss in the HPV- aBSCC group (P < 0.0001). MTOR and PIK3CA pathway GA were not significantly different in the 2 groups. Putative biomarkers associated with immunotherapy (IO) response, including MSI and TMB status, were also similar in the 2 groups. PD-L1 expression data was available for a subset of both HPV+ and HPV- cases and showed high frequencies of positive staining which was not different in the 2 groups. CONCLUSIONS: HPV+ aBSCC tends to occur more often in younger patients. As reported in other HPV-associated squamous cell carcinomas, HPV+ aBSCC demonstrates significantly reduced frequencies of inactivating mutations in cell cycle regulatory genes with similar GA in MTOR and PIK3CA pathways. The implication of HPV in the pathogenesis of bladder cancer remains unknown but warrants further exploration and clinical validation.

Biology of BCG response in non-muscle invasive bladder cancer - 2021 IBCN Updates Part III.

Bacillus Calmette-Guerin (BCG) remains the only FDA-approved first-line therapy in patients with high-risk non-muscle invasive bladder cancer. Recurrences, even after adequate BCG therapy, are common and the efficacy of second-line therapies remains modest. Therefore, early identification of patients likely to recur and treatment after recurrence remain critical unmet needs in the clinical care of bladder cancer patients. To address these deficits, a better understanding of the mechanisms of resistance to BCG-therapy is needed. The virtual update of the International Bladder Cancer Network (IBCN) on the biology of response to BCG focused on potential mechanisms and markers of resistance to intravesical BCG therapy. The insights from this meeting will be highlighted and put into context of previously reported mechanisms of resistance to BCG in this review.

Evaluation of locally manufactured patient-specific custom made implants for cranial defects using a silicone mould.

BACKGROUND: Cranial vault defects can pose a significant problem for neurosurgeons where autologous bone is no longer available for cranioplasty. Numerous materials exist to create implants which include polymethyl methacrylate (PMMA) and titanium. A technique using 3-dimensional CT scan reconstruction of a cranial defect and creating a silicon mould which can be autoclaved in theatre to create a PMMA implant was developed. OBJECTIVE: The aim of this study is to evaluate the efficacy, cosmetic result, safety and cost-effectiveness of this procedure and compare this to existing techniques. METHOD: An ambispective study was performed in patients requiring cranioplasty with a custom made implant. Patients were assessed for risk factors and cosmetic outcome, surgical technique was described and complications and cost compared to existing literature between 2010 and 2016. RESULTS: Thirty retrospective and 30 consecutive prospective patients were recruited into the study. Overall sepsis rate was 8.3%. All septic cases had superficial sepsis of which 2 grafts were removed due to cerebrospinal fluid leakage resulting in wound breakdown. A 100% accurate implant to defect ratio was achieved leading to a high satisfaction rate. Average cost was 5 times cheaper than the closest market related product. CONCLUSION: Patient specific moulds using PMMA to create custom implants are safe, have excellent cosmetic results and are a very cost-effective option to manage cranial defects. Accurate planning strategies for large craniotomies, where bone will potentially be discarded, add to surgical effectiveness and cost-saving to the patient.

CSF protein concentration associated with ventriculoperitoneal shunt obstruction in tuberculous meningitis.

INTRODUCTION: Hydrocephalus occurs in 85% of patients with tuberculous meningitis (TBM). Ventriculoperitoneal shunt (VPS) insertion is first-line treatment for relieving increased intercranial pressure. VPS obstruction secondary to increased protein levels in cerebrospinal fluid (CSF) is a known complication. OBJECTIVE: To ascertain if there is a difference in protein levels 1) between cranial and lumbar CSF, and to quantify levels associated with VPS obstruction, and 2) obtained from lumbar puncture vs. ventricular CSF. METHOD: A 30-year retrospective analysis was undertaken. CSF protein levels were statistically analysed to determine correlation between these levels and VPS obstruction. RESULTS: Of 214 children and 376 adults who underwent VPS insertion for TBM, respectively 27.5% and 25.5% sustained blocked VPS. The mean protein level in CSF collected from the non-obstructed group was 1.76 g/l, compared to 2.94 g/l in the obstructed group. The mean CSF protein level from intraoperative ventricular vs. lumbar puncture samples in the VPS obstruction group was respectively 2.471 g/l and 2.474 g/l. CONCLUSION: Patients with increased protein levels in CSF are at a high risk of VPS blockage. In these patients, temporary measures should be employed until CSF protein levels decrease.

Retraction: Thoracic Vertebral Actinomycosis Secondary to a Pulmonary Origin.

[This retracts the article DOI: 10.7759/cureus.391.].

Retraction: Staged Surgical Management in the Treatment of Primary Epidural Hydatidosis of the Spine: A Case Series and Review.

[This retracts the article DOI: 10.7759/cureus.401.].

Mitochondrial oligomers boost glycolysis in cancer stem cells to facilitate blebbishield-mediated transformation after apoptosis.

Apoptosis culminates in secondary necrosis due to lack of ATP. Cancer stem cells form spheres after apoptosis by evoking the blebbishield emergency program. Hence, determining how blebbishields avoid secondary necrosis is crucial. Here we demonstrate that N-Myc and VEGFR2 control transformation from blebbishields, during which oligomers of K-Ras, p27, BAD, Bax, and Bak boost glycolysis to avoid secondary necrosis. Non-apoptotic cancer cells also utilize oligomers to boost glycolysis, which differentiates the glycolytic function of oligomers from their apoptotic action. Smac mimetic in combination with TNF-α or TRAIL but not in combination with FasL abrogates transformation from blebbishields by inducing secondary necrosis. Thus blebbishield-mediated transformation is dependent on glycolysis, and Smac mimetics represent potential candidates to abrogate the blebbishield emergency program.

Proteus mirabilis abscess involving the entire neural axis.

Intramedullary spinal cord abscesses are rare and potentially devastating lesions usually associated with other infective processes such as bacterial endocarditis, or pulmonary or urogenital infection. We describe a 2-year-old girl who presented with an infected dermal sinus leading to an intraspinal abscess. This abscess eventually spread and involved the entire neural axis leaving her quadriparetic. Drainage of the abscess resulted in recovery and the child regained normal function of her limbs. To our knowledge this is the first documented case of an intramedullary abscess involving the entire neural axis.

Reconstructive challenges in the extended endoscopic transclival approach.

OBJECTIVE: We wanted to present our experience with the extended endoscopic approach to clival pathology, focusing on cerebrospinal fluid leak and reconstruction challenges. METHODS: We examined a consecutive series of 37 patients undergoing the extended endoscopic approach for skull base tumours, 9 patients with clival pathology. Patients were examined for the incidence of post-operative cerebrospinal fluid leak in relation to tumour pathology, location, size, reconstruction and lumbar drain. RESULTS: The overall incidence of post-operative cerebrospinal fluid leak was 10.8 per cent. Seventy-five per cent of patients who had a post-operative cerebrospinal fluid leak underwent a transclival approach (p < 0.05). All patients with clival pathology who underwent an intradural dissection had a post-operative cerebrospinal fluid leak (p < 0.05). CONCLUSION: Post-operative cerebrospinal fluid leak rates after the extended endoscopic approach have improved significantly after advancements including the vascularised nasoseptal flap. Despite this, transclival approaches continue to pose much difficulty. Further investigation is necessary to develop technical improvements that can meet the unique challenges associated with this region.

Familial colloid cyst.

Colloid cysts of the third ventricle are rare benign tumours that can present as symptomatic hydrocephalus or be an incidental finding on imaging. This report presents familial colloid cysts found in a mother and daughter. Prior examples of familial colloid cysts are also reviewed and suggestions regarding the mode of inheritance and screening strategy are proposed.

Comparative outcomes of ulnar nerve transposition versus neurolysis in patients with entrapment neuropathy at the cubital tunnel: a 20-year analysis.

BACKGROUND: Entrapment neuropathy of the ulnar nerve at the level of the elbow is the shared domain of multiple surgical specialties. A wide variety of operative methods for its surgical management have been reported. Our hospital utilizes neurolysis (NL) and subcutaneous transposition (AST). The aim of this paper was to compare the clinical outcomes in patients treated by ulnar nerve transposition versus neurolysis over a 20-year period. METHODS: We included patients who underwent either neurolysis or an ulnar nerve transposition. A retrospective analysis was performed which included 480 patients at our institution between January 1992 and December 2012. In total, physical and electronic records for 480 patients were reviewed. Three-hundred and one underwent ulnar nerve transposition and 179 underwent ulnar nerve neurolysis . RESULTS: In the AST group 201/301 patients suffered from parasthesiae pre-operatively and 156/301 had pain at and around the cubital tunnel. Paresis of the ulnar nerve innervated muscles was present in 99/301 patients. At the 3-month follow-up appointment, 187/201 patients with parasthesiae and 113/156 patients with local pain had resolution of their symptoms. In the NL group 151/179 patients had parasthesiae pre-operatively and 126/179 had pain at and around the cubital tunnel. Paresis of the ulnar nerve innervated muscles was present in 56/179 patients. At the 3-month follow-up appointment, 141/151 patients with parasthesiae and 117/126 patients with local pain had resolution of their symptoms. CONCLUSIONS: In cases of ulnar nerve compression at the cubital tunnel, both neurolysis and transposition are effective in improving clinical outcome. The only statistically significant advantage of neurolysis over transposition seems to be relief of localized elbow pain. We recommend neurolysis as the preferred procedure.

Exome Sequencing and High-Density Microarray Testing in Monozygotic Twin Pairs Discordant for Features of VACTERL Association.

Exome sequencing offers an efficient and affordable method to interrogate genetic factors involved in human disease. Performing exome sequencing of monozygotic twins discordant for VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities) association-type congenital malformations was hypothesized to potentially reveal discordant variants that could demonstrate disease cause(s). After demonstrating monozygosity, we applied high-density microarrays and exome sequencing to 2 twin pairs in which 1 twin had features of VACTERL association while the other was phenotypically normal (demonstrated through comprehensive clinical and radiological evaluation). No obvious discordant genotypic results were found that would explain phenotypic discordance. We conclude that VACTERL association is a complex disease, and while performing microarray analysis and exome sequencing on phenotypically discordant monozygotic twins may hypothetically reveal genetic causes of disorders, challenges remain in applying these methods in this circumstance.

Fluid intake, genetic variants of UDP-glucuronosyltransferases, and bladder cancer risk.

BACKGROUND: Results of studies of fluid consumption and its association with bladder cancer have been inconsistent. Few studies have considered modification effects from genetic variants that may interact with the type of consumed fluids. UDP-glucuronosyltransferases (UGTs), which are membrane-bound conjugating enzymes, catalyse the transformation of hydrophobic substrates to more water-soluble glucuronides to facilitate renal or biliary excretion. Whether genetic variants in UGTs could modulate the association between fluid intake and bladder cancer has not been studied. METHODS: We conducted a case-control study with 1007 patients with histopathologically confirmed bladder cancer and 1299 healthy matched controls. Fluid intake and epidemiologic data were collected via in-person interview. Multivariate unconditional logistic regression was used to estimate odds ratios (ORs) and the 95% confidence intervals (95% CI). RESULTS: After adjustment for potential confounders, high quantity of total fluid intake (> or =2789 vs. <1696 ml per day) conferred a 41% increased risk of bladder cancer (OR=1.41; 95% CI=1.10-1.81). Specific fluids such as regular soft drinks and decaffeinated coffee were also associated with increased risks, whereas tea, wine, and liquor were associated with decreased risks. Among 83 single-nucleotide polymorphisms in the UGT gene family, 18 were significantly associated with bladder cancer risk. The most significant one was rs7571337, with the variant genotype conferring a 29% reduction in risk (OR=0.71; 95% CI=0.56-0.90). CONCLUSIONS: Total and specific fluid intakes are associated with bladder cancer risk in the study population and that genetic variants of UGT genes could modulate the effects. These results facilitate identification of high-risk individuals and have important implications in bladder cancer prevention.

The evolution of neurosurgery: how has our practice changed?

INTRODUCTION: Neurosurgery is a rapdily evolving speciality and has often taken a lead in adopting new technologies. Advancing technology however is not the only force driving change in this discipline. Other factors include an escalation in patient expectations, an increasing (and ageing) population and the prevailing economic conditions. The aim of our study was to analyse the trends in neurosurgical practice over a 10-year period. MATERIALS AND METHODS: The details of every neurosurgical procedure performed at Wellington Regional Hospital from 2001 to 2011 were prospectively recorded in a relational database. This was then retrospectively interrogated to provide data for this study. RESULTS: Neurosurgical practice has clearly evolved over the last decade. Predictable changes include a trend towards coiling rather than clipping of cerebral aneurysms, an increasing number of tumour resections (particularly for malignant glioma) coupled with the increased use of image guidance and endoscopy. The number of operations on the cervical spine has also increased although overall the number of procedures for spinal degenerative conditions has declined, perhaps reflecting local practice. The rates of craniotomy for trauma and burr holes for chronic subdural haematoma have remained essentially unchanged. We have demonstrated a significant increase in annual case-load that is disproportionate to any change in population size. Collaboration between specialties is increasingly evident. CONCLUSION: The most important changes have occured in the fields of neuro-oncology, vascular neurosurgery and spinal surgery. Inter-specialty collaboration is establishing itself as a model of care. These data may guide resource allocation for a population increasing both in number and in age.

Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis.

Caspases mediate apoptosis and have also been implicated in stem-cell biology. How caspases are linked to stem-cell biology is not known. Here, we show that the apoptotic blebs of cancer cells fuse together to form novel structures called 'blebbishields'. Blebbishields form spheres by fusion. Both blebbishield formation and sphere formation involve active caspases and N-linked glycosylation. Sphere formation is enhanced by acidic pH and is counteracted by inhibitors of proton pump, caspases, and cholesterol. The blebbishields from VEGFR2(High) cells are capable of enhanced sphere formation. Blebbishields express transiently downregulated stem-cell markers and the sphere-forming blebbishield-derived cells are tumorigenic. Our study demonstrates that the cancer stem cells can survive after apoptosis by blebbishield formation and subsequent sphere formation.

Spinal cord compression in a patient with blue rubber bleb nevus syndrome.

Blue rubber bleb nevus syndrome is a rare condition characterised by venous malformations that affect the gastrointestinal tract and skin. There may be involvement of other organs. We describe a 70-year-old male with multiple extradural venous malformations resulting in spinal cord compression.

Severe adhesive arachnoiditis resulting in progressive paraplegia following obstetric spinal anaesthesia: a case report and review.

A 27-year-old woman developed severe adhesive arachnoiditis after an obstetric spinal anaesthetic with bupivacaine and fentanyl, complicated by back pain and headache. No other precipitating cause could be identified. She presented one week postpartum with communicating hydrocephalus and syringomyelia and underwent ventriculoperitoneal shunting and foramen magnum decompression. Two months later, she developed rapid, progressive paraplegia and sphincter dysfunction. Attempted treatments included exploratory laminectomy, external drainage of the syrinx and intravenous steroids, but these were unsuccessful and the patient remains significantly disabled 21 months later. We discuss the pathophysiology of adhesive arachnoiditis following central neuraxial anaesthesia and possible causative factors, including contamination of the injectate, intrathecal blood and local anaesthetic neurotoxicity, with reference to other published cases. In the absence of more conclusive data, practitioners of central neuraxial anaesthesia can only continue to ensure meticulous, aseptic, atraumatic technique and avoid all potential sources of contamination. It seems appropriate to discuss with patients the possibility of delayed, permanent neurological deficit while taking informed consent.

Headache after substance abuse: a diagnostic dilemma.

An 18-year-old man inhaled a substance containing synthetic cannabinoids and 1 hour later developed a severe global headache. Imaging revealed a perimesencephalic subarachnoid haemorrhage. An angiogram suggested that a small superior cerebellar artery aneurysm was the culprit. This report discusses the, as yet undefined, relationship between "herbal highs" and intracranial haemorrhage.