Idiopathic Intracranial Hypertension.

Idiopathic intracranial hypertension is defined by headaches and a decline in visual acuity due to increased intracranial pressure. Treatment options historically included weight loss, acetazolamide, and/or cerebrospinal fluid diversion surgery. Recent understanding of the contributions of dural venous sinus hypertension and stenosis has led to venous sinus stenting as a treatment option.

Single-Electrode Deep Brain Stimulation of Bilateral Posterolateral Globus Pallidus Internus in Patients With Medically Resistant Lesch-Nyhan Syndrome.

Deep brain stimulation (DBS) targeting various locations within the globus pallidus internus (GPi) is emerging as a therapeutic option for patients with medically resistant Lesch-Nyhan syndrome. We report our institutional experience with single-electrode DBS in the bilateral posterolateral GPi as an effective method for reduction of both dystonia and self-injurious behavior. Two pediatric patients aged six and 14 years underwent implantation of bilateral singular DBS leads in the posterolateral GPi and were followed postoperatively through the programming process and symptomatic improvements. Caregivers reported that after DBS in the posterolateral GPi, these patients experienced decreased self-mutilation behavior and decreased dystonia.

Surgical outcomes in large vestibular schwannomas: should cerebellopontine edema be considered in the grading systems?

PURPOSE: Large (> 3 cm) vestibular schwannomas pose complexity in surgical management because of narrow working corridors and proximity to the cranial nerves, brainstem, and inner ear structures. With current vestibular schwannoma classifications limited in information regarding cerebellopontine edema, our retrospective series examined this radiographic feature relative to clinical outcomes and its possible role in preoperative scoring. METHODS: Of 230 patients who underwent surgical resection of vestibular schwannoma (2014-2020), we identified 107 patients with Koos grades 3 or 4 tumors for radiographic assessment of edema in the middle cerebellar peduncle (MCP), brainstem, or both. Radiographic images were graded and patients grouped into Koos grades 3 or 4 or our proposed grade 5 with edema. Tumor volumes, radiographic features, clinical presentations, and clinical outcomes were evaluated. RESULTS: The 107 patients included 22 patients with grade 3 tumors, 39 with grade 4, and 46 with grade 5. No statistical differences were noted among groups for demographic data or complication rates. Unlike grades 3 and 4 patients, grade 5 patients presented with worse hearing (p < 0.001), larger tumors (p < 0.001), lower rates of gross total resection (GTR), longer hospital stays, and higher rates of balance dysfunction. CONCLUSION: With edema detected in 43% of this cohort, special considerations are warranted for grade 5 vestibular schwannomas given the preoperative findings of worse hearing, lower GTR rates, longer hospital stays, and 96% who pursued postoperative balance therapy. We propose that grade 5 with edema offers a more nuanced interpretation of a radiographic feature that holds relevance to treatment selection and patient outcomes.

Multiple painful plaques and the Sweet's syndrome.

We present a rare case of Sweet's syndrome. A 39-year-old woman with subjective fevers, polyarthralgia, and malaise presented with worsening painful erythematous plaques on the trunk, arms, and legs. Further examination with biopsy revealed a diagnosis of acute febrile neutrophilic dermatosis, or Sweet's syndrome. Diagnosis by skin biopsy is crucial, and onset requires prompt evaluation for serious associated disorders such as leukemias, inflammatory bowel disease, thyroid disease, sarcoidosis, and infectious etiologies. In general, symptoms and cutaneous manifestations of Sweet syndrome respond rapidly to treatment with systemic corticosteroids or potassium iodide.

Management of full-thickness skin grafts.

Full-thickness skin grafts are a commonly used reconstructive method following Mohs micrographic surgery. The literature varies on the most appropriate methods of suturing and securing grafts as well as best practices to dress the graft postoperatively. Our objective was to review various approaches to management of full-thickness skin grafts, including suturing the graft, securing the graft, and topical emollient use on the graft postoperatively. It was found that absorbable sutures, plain gut, provide preferable outcomes with full-thickness skin grafts. The tie-over bolster is the most-used method for securing skin grafts after placement, although several other methods have demonstrated efficacy, including the polyurethane foam, sandwich, and quilting suture methods. While various topical emollients are used in the immediate postoperative period, plain white petrolatum is the least likely to form allergic contact dermatitis.

Is your patient a candidate for Mohs micrographic surgery?

This guide for family physicians describes the advantages of Mohs surgery and which patients make good candidates for the procedure.

A Comparison of the Short-term Outcomes of Three Flap Reconstruction Techniques Used After Beyond Total Mesorectal Excision Surgery for Anorectal Cancer.

BACKGROUND: Surgery for advanced or recurrent pelvic malignancy can result in perineal defects that cannot be closed by wound edge approximation. Myocutaneous flaps can fill the defect and accelerate healing. No reconstruction has been proven to be superior to the others. OBJECTIVE: This study aimed to compare 3 flap procedures after beyond total mesorectal excision surgery. DESIGN: This is a retrospective analysis of a prospective database, according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. SETTINGS: This study was performed at a tertiary hospital. PATIENTS: Consecutive series of patients who required flap reconstruction after beyond total mesorectal excision surgery between 2007 and 2016 were included. MAIN OUTCOME MEASURES: Short-term outcomes after oblique rectus abdominis flap vs vertical rectus abdominis flap vs inferior gluteal artery perforator flap reconstruction were evaluated. RESULTS: Included are 65 (59%) oblique rectus abdominis flap, 30 (27.3%) vertical rectus abdominis flap, and 15 (13.7%) inferior gluteal artery perforator flap outcomes. Sacrectomy was performed in 12 (18.5%), 10 (33.3%), and 8 (53.3%) patients (p = 0.016). Preoperative radiotherapy was used in 60 (92.3%), 26 (86.7%), and 11 (73.3%) patients (p = 0.11). Flap infection and dehiscence occurred in 7 (10.8%), 1 (3.3%), and 4 (26.7%) patients. There was an increased risk of flap complication with inferior gluteal artery perforator flap vs vertical rectus abdominis flap (p = 0.036). Inferior gluteal artery perforator flap (OR, 6.26; p = 0.02) and obesity (OR, 4.96; p = 0.02) were associated with flap complications. Only complications of the oblique rectus abdominis flap decreased significantly over time (p = 0.03). The length of stay and complete (R0) resection rate were not different between the groups. LIMITATIONS: This study was limited because of its retrospective nature and because it was conducted at a single center. CONCLUSIONS: The techniques appear comparable. The approaches should be considered complementary, and the choice should be individualized. See Video Abstract at http://links.lww.com/DCR/B141. COMPARACIÓN DE RESULTADOS A CORTO PLAZO DE TRES TÉCNICAS DE RECONSTRUCCIÓN CON COLGAJO UTILIZADAS DESPUÉS DE LA CIRUGÍA DE ESCISIÓN MESORRECTAL TOTAL EXTENDIDA PARA EL CÁNCER ANORRECTAL: La cirugía para malignidad pélvica avanzada o recurrente puede provocar defectos perineales, que no pueden cerrarse por aproximación de los bordes de la herida. Los colgajos miocutáneos pueden llenar el defecto y acelerar la curación. Ninguna reconstrucción ha demostrado ser superior a las demás.Comparar tres procedimientos de colgajo después de una cirugía de escisión mesorrectal total extendida.Análisis retrospectivo de una base de datos prospectiva, de acuerdo con la Declaración de Fortalecimiento de los informes de estudios observacionales en epidemiología.Hospital de tercer nivel.Series consecutivas de pacientes que requirieron reconstrucción con colgajo después de una cirugía de escisión mesorrectal total extendida entre 2007 y 2016.Resultados a corto plazo después del colgajo oblicuo recto abdominal versus colgajo vertical recto abdominal versus reconstrucción del colgajo perforador de la arteria glútea inferior.Se incluyen 65 (59%) colgajo oblicuo recto abdominal oblicuo, 30 (27.3%) colgajo vertical recto abdominal y 15 (13.7%) colgajo perforador de la arteria glútea inferior. Sacrectomía se realizó en 12 (18.5%), 10 (33.3%) y 8 (53.3%) pacientes respectivamente (p = 0.016). La radioterapia preoperatoria se utilizó en 60 (92.3%), 26 (86.7%) y 11 (73.3%) (p = 0,11). La infección del colgajo y la dehiscencia ocurrieron en 7 (10.8%), 1 (3.3%) y 4 (26.7%). Hubo un mayor riesgo de complicación con el colgajo perforador de la arteria glútea inferior en comparación al colgajo vertical del recto abdominal (p = 0.036). El colgajo perforador de la arteria glútea inferior (OR 6.26, p = 0.02) y la obesidad (OR 4.96, p = 0.02) se asociaron con complicaciones del colgajo. Solo las complicaciones del colgajo oblicuo recto abdominal disminuyeron significativamente con el tiempo (p = 0.03). La duración de la estancia hospitalaria y la tasa de resección completa (R0) no fue diferente entre los grupos.Estudio retrospectivo en centro único.Las técnicas parecen comparables. Los enfoques deben considerarse complementarios y la elección individualizada. Consulte Video Resumen en http://links.lww.com/DCR/B141.

Length-dependent toxicity of TiO2 nanofibers: mitigation via shortening.

Length and aspect ratio represent important toxicity determinants of fibrous nanomaterials. We have previously shown that anatase TiO2 nanofibers (TiO2 NF) cause a dose-dependent decrease of cell viability as well as the loss of epithelial barrier integrity in polarized airway cell monolayers. Herein we have investigated the impact of fiber shortening, obtained by ball-milling, on the biological effects of TiO2 NF of industrial origin. Long TiO2 NF (L-TiO2 NF) were more cytotoxic than their shortened counterparts (S-TiO2 NF) toward alveolar A549 cells and bronchial 16HBE cells. Moreover, L-TiO2 NF increased the permeability of 16HBE monolayers and perturbed the distribution of tight-junction proteins, an effect also mitigated by fiber shortening. Raw264.7 macrophages efficiently internalized shortened but not long NF, which caused cell stretching and deformation. Compared with L-TiO2 NF, S-TiO2 NF triggered a more evident macrophage activation, an effect suppressed by the phagocytosis inhibitor cytochalasin B. Conversely, a significant increase of inflammatory markers was detected in either the lungs or the peritoneal cavity of mice exposed to L-TiO2 NF but not to S-TiO2 NF, suggesting that short-term macrophage activation in vitro may not be always a reliable indicator of persistent inflammation in vivo. It is concluded that fiber shortening mitigates NF detrimental effects on cell viability and epithelial barrier competence in vitro as well as inflammation development in vivo. These data suggest that fiber shortening may represent an effective safe-by-design strategy for mitigating TiO2 NF toxic effects.

Scaffold Morphing Identifies 3-Pyridyl Azetidine Ureas as Inhibitors of Nicotinamide Phosphoribosyltransferase (NAMPT).

Small molecules that inhibit the metabolic enzyme NAMPT have emerged as potential therapeutics in oncology. As part of our effort in this area, we took a scaffold morphing approach and identified 3-pyridyl azetidine ureas as a potent NAMPT inhibiting motif. We explored the SAR of this series, including 5 and 6 amino pyridines, using a convergent synthetic strategy. This lead optimization campaign yielded multiple compounds with excellent in vitro potency and good ADME properties that culminated in compound 27.

Predictors of short-term readmission after beyond total mesorectal excision for primary locally advanced and recurrent rectal cancer.

Unplanned readmissions heavily affect the cost of health care and are used as an indicator of performance. No clear data are available regarding beyond-total mesorectal excision (bTME) procedure. Aim of the study is to identify patient-related and surgery-related factors influencing the 30-day readmissions after bTME. Retrospective data were collected from 220 patients who underwent bTME procedures at single centre between 2006 and 2016. Patient-related and operative factors were assessed, including body mass index (BMI), age, gender, American Society of Anaesthesiologists' (ASA) score, preoperative stage, neo-adjuvant therapy, primary tumour vs recurrence, the extent of surgery. The readmission rate was 8.18%. No statistically significant association was found with BMI, ASA score, length of stay and stay in the intensive care unit, primary vs recurrent tumour or blood transfusions. Not quite statistically significant was the association with pelvic side wall dissection (OR 3.32, p = 0.054). Statistically significant factors included preoperative stage > IIIb (OR: 4.77, p = 0.002), neo-adjuvant therapy (OR: 0.13, p = 0.0006), age over 65 years (OR: 5.96, p = 0.0005), any re-intervention during the first admission (OR: 7.4, p = 0.0001), and any post-operative complication (OR: 9.01, p = 0.004). The readmission rate after beyond-TME procedure is influenced by patient-related factors as well as post-operative morbidity.

A systematic review and network meta-analysis comparing treatments for faecal incontinence.

BACKGROUND: Although numerous treatments exist for fecal incontinence (FI), no consensus exists on the best treatment strategy. The aim was to review the literature and to compare the clinical outcomes and effectiveness of treatments available for FI. MATERIALS AND METHOD: A systematic literature review was performed, from inception to May 2018, of the following databases: MEDLINE, EMBASE, Science Citation Index Expanded, Cochrane Library. The search terms used were "faecal incontinence" and "treatment". Only randomized controlled trials (RCTs) comparing treatments for FI were considered. A Bayesian network meta-analysis was performed using the Markov chain Monte Carlo method. RESULT: Forty-seven RCTs were included comparing 37 treatments and reporting on 3748 participants. No treatment ranked best or worst with high probability for any outcome of interest. No significant difference was identified between treatments for frequency of FI per week, or in changing the resting pressure, maximum resting pressure, squeeze pressure, and maximum squeeze pressure. Radiofrequency resulted in more adverse events compared to placebo. Sacral nerve stimulation (SNS) and zinc-aluminium improved the fecal incontinence quality of life questionnaire (FIQL) lifestyle, coping, and embarrassment domains compared to placebo. Transcutaneous posterior tibial nerve stimulation (TPTNS) improved the FIQL embarrassment domain compared to placebo. Autologous myoblasts and zinc-aluminium improved the FIQL depression domain compared to placebo. SNS, artificial bowel sphincter (ABS), and zinc-aluminium significantly improved incontinence scores compared to placebo. Injection of non-animal stabilized hyaluronic acid/dextranomer (NASHA/Dx) resulted in more patients with ≥50% reduction in FI episodes compared to placebo. CONCLUSION: SNS, ABS, TPTNS, NASHA/Dx, zinc-aluminium, and autologous myoblasts resulted in isolated improvements in specific outcomes of interest. No difference was identified in incontinence episodes, no treatment ranked best persistently or persistently improved outcomes, and many included treatments did not significantly benefit patients compared to placebo. Large multicentre RCTs with long-term follow-up and standardized inclusion criteria and outcome measures are needed.

The obesity paradox in beyond total mesorectal excision surgery for locally advanced and recurrent rectal cancer.

The objective is to investigate preoperative body mass index (BMI) in patients receiving beyond total mesorectal excision (bTME) surgery. The primary end point is length of postoperative stay. Secondary end points are length of intensive care stay, postoperative morbidity and overall survival. BMI is the most commonly used anthropometric measurement of nutrition and studies have shown that overweight and obese patients can have improved surgical outcomes. Patients who underwent a bTME operation for locally advanced or recurrent rectal cancer were put into three BMI (kg/m2) groups of normal weight (18.5-24.9), overweight (25-29.9) and obese (≥ 30) for analysis. Included are 220 consecutive patients from a single centre. The overall length of stay, in days ± standard deviation (range), for normal weight, overweight and obese patients was 21.14 ± 16.4 (6-99), 15.24 ± 4.3 (7-32) and 19.10 ± 9.8 (8-62) respectively (p = 0.002). The mean ICU length of stay was 5.40 ± 9.1 (1-69), 3.37 ± 2.4 (0-19) and 3.60 ± 2.4 (1-14), respectively (p = 0.030). There was no significant difference between the three groups in terms of postoperative morbidity or overall survival. Patients with a normal weight BMI in this cohort have a significantly longer length of stay in ICU and in hospital than overweight or obese patients. This is seen with no significant difference in morbidity or overall survival.

In Vivo Femtosecond Laser Subsurface Cortical Microtransections Attenuate Acute Rat Focal Seizures.

Recent evidence shows that seizures propagate primarily through supragranular cortical layers. To selectively modify these circuits, we developed a new technique using tightly focused, femtosecond infrared laser pulses to make as small as ~100 µm-wide subsurface cortical incisions surrounding an epileptic focus. We use this "laser scalpel" to produce subsurface cortical incisions selectively to supragranular layers surrounding an epileptic focus in an acute rodent seizure model. Compared with sham animals, these microtransections completely blocked seizure initiation and propagation in 1/3 of all animals. In the remaining animals, seizure frequency was reduced by 2/3 and seizure propagation reduced by 1/3. In those seizures that still propagated, it was delayed and reduced in amplitude. When the recording electrode was inside the partially isolated cube and the seizure focus was on the outside, the results were even more striking. In spite of these microtransections, somatosensory responses to tail stimulation were maintained but with reduced amplitude. Our data show that just a single enclosing wall of laser cuts limited to supragranular layers led to a significant reduction in seizure initiation and propagation with preserved cortical function. Modification of this concept may be a useful treatment for human epilepsy.

Structure based design of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors from a phenotypic screen.

Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo.

Discrepancies between NCCN and ESMO guidelines in the management of anal cancer: a qualitative review.

There is an ever-growing need, with the ongoing developments in research and the progress towards patient centered care, to delineate standardized protocols of management of anal cancer. However, guidelines from different societies show some degree of disagreement. This is a systematic review of the literature to identify similarities and discrepancies between the guidelines for the management of anal cancer drafted by the European Society for Medical Oncology (ESMO) and by the National Comprehensive Cancer Network (NCCN). We found essentially similar management for investigation, diagnosis, chemotherapy regimens, and radiotherapy doses in both ESMO and NCCN recommendations in the management of anal cancer. There were few differences, which included the levels of evidence and grades of recommendations, the delineation of radiotherapy fields, and the treatment of the elderly and personalized medicine based on genetics. The follow-up regime is also marginally different in the first 2 years. Even if the observed differences may be justified by a different implementation of evidence-based medicine among different countries for particular management modalities of anal cancer, we identified the grey areas which need further study. In addition, these facets should be assessed more carefully when planning future guidelines.

Colorectal cancer diagnosed during pregnancy: systematic review and treatment pathways.

The aim of this study was to identify the mode of presentation and incidence of colorectal cancer in pregnancy (CRC-p), assess the outcomes of the mother and foetus according to gestational age, treatment delivered and cancer features and location. A systematic review of the literature was carried out to identify studies reporting on CRC-p and pooled analysis of the reported data. Seventy-nine papers reporting on 119 patients with unequivocal CRC-p were included. The calculated pooled risk is 0.002% and age at diagnosis has decreased over time. The median age at diagnosis was 32 (range, 17-46) years. Twelve per cent, 41 and 47% of CRC-p were diagnosed during the first, second and third trimester. The CRC-p site was the colon in 53.4% of cases, the rectum in 44% and multiple sites in 2.6%. Bleeding occurred in 47% of patients, abdominal pain in 37.6%, constipation in 14.1%, obstruction in 9.4% and perforation in 2.4%. Out of 82 patients whose treatment was described, 9.8% received chemotherapy during pregnancy. None of their newborns developed permanent disability, one developed hypothyroidism and 72% of newborns were alive. Vaginal delivery was possible in 60% of cases. Anterior resection was performed in 30% of patients and abdominoperineal excision of the rectum in 14.9%. Five patients had either synchronous (60%) or metachronous liver resection (40%). The median survival in these patients was 42 (0-120) months. Fifty-five per cent of patients were alive at the last available follow-up. The median survival of the mother was 36 (0-360) months. Patients with rectal cancer had longer survival compared with patients with colon cancer (P=0.0072). CRC-p is rare, leading to symptoms being overlooked, and diagnosis made at advanced stages. Cases described in the literature include patients who had cancer before pregnancy or developed it after delivery. Survival has not increased over time and the management of these patients requires collaboration between specialties and active interaction with the patients.

Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity.

Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1R132H mutation destabilizes an IDH1 "regulatory segment," which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity. We also report crystal structures of oncogenic IDH2 mutant isoforms, highlighting the fact that the analogous segment of IDH2 is not similarly destabilized. This intrinsic stability of IDH2 may contribute to observed inhibitor IDH1 isoform selectivity. Moreover, discrete residues in the IDH1 allosteric pocket that differ from IDH2 may also guide IDH1 isoform selectivity. These data provide a deeper understanding of how IDH1 inhibitors achieve mutant and isoform selectivity.

A Systematic Review to Assess Resection Margin Status After Abdominoperineal Excision and Pelvic Exenteration for Rectal Cancer.

OBJECTIVE: The aim of this study was to assess resection margin status and its impact on survival after abdominoperineal excision and pelvic exenteration for primary or recurrent rectal cancer. SUMMARY OF BACKGROUND DATA: Resection margin is important to guide therapy and to evaluate patient prognosis. METHODS: A meta-analysis was performed to assess the impact of resection margin status on survival, and a regression analysis to analyze positive resection margin rates reported in the literature. RESULTS: The analysis included 111 studies reporting on 19,607 participants after abdominoperineal excision, and 30 studies reporting on 1326 participants after pelvic exenteration. The positive resection margin rates for abdominoperineal excision were 14.7% and 24.0% for pelvic exenteration. The overall survival and disease-free survival rates were significantly worse for patients with positive compared with negative resection margins after abdominoperineal excision [hazard ratio (HR) 2.64, P < 0.01; HR 3.70, P < 0.01, respectively] and after pelvic exenteration (HR 2.23, P < 0.01; HR 2.93, P < 0.01, respectively). For patients undergoing abdominoperineal excision with positive resection margins, the reported tumor sites were 57% anterior, 15% posterior, 10% left or right lateral, 8% circumferential, 10% unspecified. A significant decrease in positive resection margin rates was identified over time for abdominoperineal excision. Although positive resection margin rates did not significantly change with the size of the study, some small size studies reported higher than expected positive resection margin rates. CONCLUSIONS: Resection margin status influences survival and a multidisciplinary approach in experienced centers may result in reduced positive resection margins. For advanced anterior rectal cancer, posterior pelvic exenteration instead of abdominoperineal excision may improve resection margins.