A molecularly integrated grade for meningioma

BackgroundMeningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management.MethodsWe evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms.ResultsWe developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score.ConclusionWe propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.     

Health care utilization related to the introduction of designated GPs at care homes in Denmark: a register-based study

ObjectiveTo investigate the correlation between having designated general practitioners (GPs) in residential care homes and the residents’ number of contacts with primary care, number of hospital admissions and mortality.DesignA retrospective register-based longitudinal study.SettingForty-two care homes in Aarhus Municipality, Denmark.SubjectsA total of 2376 care home residents in the period from 1 September 2016 to 31 December 2018.Main outcome measuresWe used two models to calculate the incidence risk ratio (IRR) for primary care contacts, hospital admission or dying. Model 1 compared the residents’ risk time before with their risk time after implementation of the designated GP model. Model 2 included only risk time after implementation and was based on calculations of successful (rate ≥60%) implementation.ResultsWeighted by time at risk, the proportion of females across the two models ranged from 64% to 68%. The largest group was aged ‘85-94’ years. In Model 1, the mere implementation of the model did not correlate with changes in primary care contacts, hospital admissions, or mortality. Contrarily, in Model 2, residents living in care homes with successful implementation had fewer email contacts (IRR = 0.81, 95%CI: 0.68;0.96), fewer telephone contacts (IRR = 0.78, 95%CI: 0.68;0.90) and fewer hospital admissions (IRR = 0.85, 95%CI: 0.73;0.99), but more home visits (IRR = 1.70, 95%CI: 1.29;2.25) than residents living in care homes with lower implementation rates.ConclusionThe designated GP model seems promising, as a high implementation degree of the model correlated with a reduced the number of acute admissions, short-term admissions and readmissions. Future studies should focus on gaining deeper insight into the mechanisms of the designated GP model to further optimize the model.

Key points

• A new care model was introduced in Denmark in 2017, designating dedicated GPs to residential care homes for the elderly.
• Successful implementation correlated with significantly fewer hospital admissions, specifically for acute admissions, but also with fewer short-term admissions and readmissions.
• The implementation of the model correlated significantly with fewer e-mail and telephone contacts and with more home visits.
• Future studies should gain more insight into the mechanisms of the designated GP model to further optimize the model.

     

Stability of osteochondral fragments of the femoral condyle: magnetic resonance imaging with histopathologic correlation in an animal model

The stability of surgically induced osteochondral fragments of the femoral condyle was examined by magnetic resonance imaging (MRI) using T1- and T2-weighted spin echo sequences in 7 dogs; contrast-enhanced T1-weighted spin-echo sequences were also obtained. Animals were sacrificed between the 34th and 196th day after surgery. MR images were compared with the histopathologic findings. Two loose and five stable fragments were found after injection of contrast medium. With the loose fragments, a well-defined line of high signal intensity between the fragment and the epiphysis showed marked enhancement. Histological examination revealed vascularized granulation tissue at the interface. Stable fragments also showed a similar, but irregularly defined line on plain sequences, but no enhancement after injection of contrast medium; histological examination showed no granulation tissue at the interface but intact bone trabeculae within the completely repaired fracture. Fibrocartilaginous repair at the articular cartilage surface also showed enhancement. Contrast-enhanced MR imaging allowed an exact delineation of the line of separation of unstable osteochondral fragments in this animal model with differentiation from a similar line occurring in stable fragments. However, this interface line in relation to stable fragments could not be explained histologically and probably reflects differences of binding or distribution of protons in healing osteochondral fragments.     

Hematopoietic reconstitution after bone marrow transplantation: Assessment with MR imaging and H-1 localized spectroscopy

Magnetic resonance (MR) studies were performed in 14 patients as early as possible (21–110 days) after bone marrow transplantation (BMT). MR characteristics of lumbar vertebral bone marrow were studied with T1-weighted spin-echo imaging, water- and fatselective imaging with a frequency-selective excitation technique, and point-resolved spatially localized proton spectroscopy. Signals from water and fat protons and their T1 and T2 values were analyzed. Water proton signal intensity correlated well with cellularity within bone marrow, as determined with parallel iliac crest biopsies. The fraction of signal from water in red bone marrow of patients with allogeneic transplants from siblings (four cases) was significantly higher than in four patients with autologous transplants. The latter showed very low cellularity in the period of about 4 weeks after BMT because of the cytotoxic pretreatment of the bone marrow. The MR results in six patients with allogeneic transplants from unrelated donors ranged widely, depending on the complications after BMT. Analysis of data obtained with the different techniques showed that water- and fat-selective MR imaging and spectroscopic methods are useful for noninvasive monitoring of hematopoietic reconstitution after BMT.     

Trends in adrenal surgery: institutional review of 528 consecutive adrenalectomies

Purpose

The increasing detection of adrenal tumors and the availability of a more sophisticated biochemical work-up leading to rising numbers of sub-clinical Conn’s and Cushing’s syndromes coincide with a rising number of adrenalectomies worldwide. The aim of our study was to report a single institution’s experience with adrenal surgery.

Methods

We report data of 528 adrenalectomies, operated at our institution before and after the onset of minimally invasive endoscopic surgery (1986–1994, 1995–2008). Gender, age, indication, imaging, surgical approach, operating time, histology, tumor size, hospital stay, and complications were analyzed retrospectively.

Results

A total of 478 patients underwent adrenal surgery during the time observed. The average number of yearly adrenalectomies increased from 14 to 21 (p?=?0.001) after the onset of laparoscopic surgery. Imaging techniques showed a significant shift towards magnetic resonance imaging (p?<?0.001) and preoperative assessment of tumor size was significantly correlated to malignancy: 10.8?% (11/102) and 42?% (21/50) of tumors measuring 4–6?cm and ≥6 cm, respectively, were malignant in the final histology report (p?<?0.001). Patients operated by minimally invasive endoscopy were significantly younger (mean 49.4?years, p?=?0.046), had significantly shorter operating times (mean 118?min, p?<?0.001), had shorter hospital stays (mean 7.1?days, p?<?0.001), and had less complications (6.9?%, p?=?0.004) compared to patients resected through open procedures.

Conclusion

Although adrenalectomy rates increased and minimally invasive endoscopic surgery reduced hospital stay and complications at our institution, the yearly number of procedures was still low with often high surgical complexity. We therefore believe that adrenal surgery remains a highly specialized procedure that should preferably be performed at endocrine surgery centers.     

Normalization of serum bile acids after partial external biliary diversion indicates an excellent long-term outcome in children with progressive familial intrahepatic cholestasis

Background/PurposeThe surgical treatment for patients with progressive familial intrahepatic cholestasis (PFIC) is either liver transplantation (LTX) or partial external biliary diversion (PEBD). Both procedures achieve a good short-term outcome. However, the treatment strategy for these children remains controversial because the long-term outcome after PEBD is unknown. The aim of our study was to assess the long-term outcome and complications after PEBD in our institution.MethodsWe retrospectively analyzed the characteristics of all patients with PFIC undergoing PEBD in our department from 1994 to 2008. The course of serum bile acids, pruritus, and liver enzymes was assessed in a regular follow-up.ResultsTwenty-four patients underwent PEBD. Thirteen patients (54%) improved significantly, with a normalization of serum bile acids (P < .001 vs postoperatively) and lessened pruritus (P < .05 vs preoperatively) at 12 months after PEBD. None of these patients showed progression of cholestasis during a median follow-up of 9.8 years (range, 1.6-14.3 years). Partial external biliary diversion failed to normalize bile acids in 11 patients, of whom 9 required secondary LTX at a 1-year follow-up, with a median interval of 1.9 years (range, 0.5-3.8 years). All 7 patients (100%) with liver cirrhosis at the time of PEBD and 2 of 17 patients without cirrhosis (12%) required secondary LTX (P < .001).ConclusionsClinical improvement with normalization of serum bile acids within 1 year was associated with an excellent long-term outcome in patients with PEBD. The presence of liver cirrhosis at the time of PEBD indicated an unfavorable outcome. Thus, we recommend primary LTX only in PFIC patients with liver cirrhosis.     

Effects of unisegmental disc compression on adjacent segments: an in vivo animal model

It is controversial whether fusion of discs in the spine leads to increased degeneration on the remaining discs or whether the degenerative changes are merely a part of the inevitable natural history process. To determine the effects of unisegmental compression and subsequent recovery on adjacent segments, we studied histology, radiology and intradiscal pressure using an in vivo rabbit model. Fifteen New Zealand rabbits were divided in to three groups of five. In the first group, the intervertebral disc L4–L5 of the lumbar spine was axially loaded for 28 days with an external loading device. In the second group, the intervertebral disc was compressed for 28 days and allowed to recover for an equal amount of time, with the loading device removed. Five animals underwent a sham operation, in which the external loading device was situated, but their discs remained unloaded for 28 days. The intradiscal pressure was determined in the loaded discs as well as in the cranial and caudal adjacent discs. Lateral radiographs were taken from each subjected intervertebral disc with adjacent vertebral bodies and the cranial and caudal adjacent segments. The compressed discs showed lower intradiscal pressure in comparison with the control group, which remained unloaded. In the cranial and caudal discs adjacent to the loaded discs the average intradiscal pressure was similar to the unloaded controls. The loaded discs demonstrated a significant decrease in disc space. No discs adjacent to the loaded discs changed in height. The lamellar architecture of the inner, middle, and outer annulus became more disorganized in the loaded discs. The nucleus pulposus showed increase of mucoid degeneration and increased cell death. Intervertebral discs from the control group and the adjacent discs to the compressed discs maintained their normal morphology. This study shows that mechanical loading of discs in the spine can cause rapid degeneration. Adjacent discs, however, did not change in terms of radiology, intradiscal pressure, or histology.     

Long-term outcome after Bascom's cleft-lift procedure under tumescent local analgesia for pilonidal sinus disease: a cohort study

Aim

Bascom's cleft-lift procedure for pilonidal sinus disease under tumescent local analgesia is feasible and well tolerated with favourable short-term outcomes. We aimed to assess the 10-year treatment success rate after cleft-lift under tumescent local analgesia.

Method

This was a single-centre cohort study based on prospectively registered perioperative data and survey data with additional data from electronic medical records. The cleft-lift procedure was performed under tumescent local analgesia in a day-surgical setting at a tertiary referral hospital between 1 July 2008 and 31 March 2014. The primary outcome was the 10-year risk treatment success defined as complete wound healing within 180 days of surgery or no recurrence assessed with competing risk analyses. Secondary outcomes were time to complete wound healing, persistent pain and cosmetic satisfaction.

Results

Two hundred patients with complex pilonidal sinus disease were included. Indication was incomplete wound healing after pilonidal sinus surgery in 43 (21.5%) patients, recurrence after previous intervention in 78 (39.0%) or moderate to complex sinuses assessed by a consultant surgeon in 79 (39.5%). One hundred and ninety-five patients had complete wound healing within 180 days with a median time of 29 days (interquartile range 16–47). The cumulative risk of 10-year recurrence was 11.3% (95% CI 6.2%–16.4%) with a median follow-up time of 8.5 (1.0–10.7) years. Treatment success was 86.1% (95% CI 80.6%–91.5%). No significant predictors were associated with recurrence, and 90% of patients experienced no persistent pain.

Conclusion

Cleft-lift performed under tumescent local analgesia has an acceptable 10-year treatment failure rate, making the method feasible in a day-surgery setting.     

Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis

Background and purpose

Human Papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) respond favourably to radiotherapy as compared to HPV-unrelated HNSCC. We investigated DNA damage response in HPV-positive and HPV-negative HNSCC cell lines aiming to identify mechanisms, which illustrate reasons for the increased sensitivity of HPV-positive cancers of the oropharynx.

Methods

Radiation response including clonogenic survival, apoptosis, DNA double-strand break (DSB) repair, and cell cycle redistribution in four HPV-positive (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (UD-SCC-1, UM-SCC-6, UM-SCC-11b, UT-SCC-33) cell lines was evaluated.

Results

HPV-positive cells were more radiosensitive (mean SF2: 0.198 range: 0.22–0.18) than HPV-negative cells (mean SF2: 0.34, range: 0.45–0.27; p?=?0.010). Irradiated HPV-positive cell lines progressed faster through S-phase showing a more distinct accumulation in G2/M. The abnormal cell cycle checkpoint activation was accompanied by a more pronounced increase of cell death after x-irradiation and a higher number of residual and unreleased DSBs.

Conclusions

The enhanced responsiveness of HPV-related HNSCC to radiotherapy might be caused by a higher cellular radiosensitivity due to cell cycle dysregulation and impaired DNA DSB repair.     

Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1

The risk of diabetic nephropathy is partially genetically determined. Diabetic nephropathy is linked to a gene locus on chromosome 18q22.3-q23. We aimed to identify the causative gene on chromosome 18 and to study the mechanism by which the product of this gene could be involved in the development of diabetic nephropathy. DNA polymorphisms were determined in 135 case (diabetic nephropathy) and 107 control (diabetes without nephropathy) subjects. The effect of carnosine on the production of extracellular matrix components and transforming growth factor-beta (TGF-beta) after exposure to 5 and 25 mmol/l d-glucose was studied in cultured human podocytes and mesangial cells, respectively. A trinucleotide repeat in exon 2 of the CNDP1 gene, coding for a leucine repeat in the leader peptide of the carnosinase-1 precursor, was associated with nephropathy. The shortest allelic form (CNDP1 Mannheim) was more common in the absence of nephropathy (P = 0.0028, odds ratio 2.56 [95% CI 1.36-4.84]) and was associated with lower serum carnosinase levels. Carnosine inhibited the increased production of fibronectin and collagen type VI in podocytes and the increased production of TGF-beta in mesangial cells induced by 25 mmol/l glucose. Diabetic patients with the CNDP1 Mannheim variant are less susceptible for nephropathy. Carnosine protects against the adverse effects of high glucose levels on renal cells.