Progesterone

Progesterone

see also Progesterone receptor.

(pregn-4-ene-3,20-dione; abbreviated as P4) is an endogenous steroid hormone involved in the menstrual cyclepregnancy, and embryogenesis of humans and other species.

It belongs to a group of steroid hormones called the progestogens, and is the major progestogen in the body. Progesterone is also a crucial metabolic intermediate in the production other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a neurosteroid.


Dexamethasone (DEXA) is widely used in the management of peritumoral edema. DEXA, however, has many systemic side-effects, and may interact negatively with glioma therapy. Progesterone (PROG), on the other hand, is a well-tolerated and readily accessible antiinflammatory and anti-edema agent with potent neuroprotective properties.

Cheng et al., investigated if PROG can serve as a viable alternative to DEXA in the management of peri-tumoral brain edema.

They used an orthotopic C6 glioblastoma model with male Sprague Dawley rats. Tumor grafts were allowed to grow for 14 days prior to drugtreatment with (i) DEXA 1mg/kg, (ii) PROG 10mg/kg or (iii) PROG 20 mg/kg for five consecutive days. Overall animal survival and neurologic functions were evaluated. Mechanistic studies on blood brain barrier (BBB) permeability and angiogenic responses were performed on the ex vivo tumor grafts.

They found that all drug treatments prolonged overall survival to different extents. PROG 10mg led to significantly longer survival, and better preservation of neurologic functions and body weightBBB permeability was better preserved with PROG 10mg than DEXA possibly through the downregulation of MMP-9 and AQP-4 expressions; anti-angiogenic responses were also observed in the PROG group.

This proof-of-concept pilot study provides novel information on the use of PROG as a corticosteroids-sparing agent in brain tumor management. Further translational and clinical studies are warranted 1).

Progesterone for acute traumatic brain injury

1)

Cheng Y, Yeung WL, De Zhang P, Li N, Kiang MY, Leung KK. Progesterone is more effective than dexamethasone in prolonging overall survival and preserving neurologic functions in experimental animals with orthotopic glioblastoma allografts. World Neurosurg. 2019 Jan 30. pii: S1878-8750(19)30211-6. doi: 10.1016/j.wneu.2019.01.113. [Epub ahead of print] PubMed PMID: 30710720.

EGFR Non small cell lung cancer intracranial metastases

EGFR Non small cell lung cancer intracranial metastases

Advances in our understanding of genomic alterations in lung cancer have led to the discovery of several driver mutations in non small cell lung cancer 1). The most common are the EGFR activating mutations, which are present in 50% of patients of Asian descent and in 10%–15% of white patients with NSCLC of adenocarcinoma histology 2).

Huang et al., investigated whether tumor mutation status (EGFRKRASALKROS1BRAF) and treatment history were associated with survivalafter neurosurgery.

They reviewed the electronic health records of 104 non small cell lung cancer (NSCLC) patients with genomic profiling who underwent neurosurgical resection for symptomatic brain metastases at an academic institution between January 2000 and January 2018.

They used multivariate Cox proportional hazards models to evaluate the association between overall survival (OS) after neurosurgery and clinico-pathological factors including mutation status.

Mean age of patients in this study was 61 (±12) years, and 44% were men. The median OS after neurosurgery was 24 months (95% confidence interval: 18-34). Our multivariate analysis showed that the presence of an EGFR mutation in the tumor was significantly associated with improved OS (hazard ratio [HR] 0.214 p = 0.029), independent of tyrosine kinase inhibitor (TKI) use. Presence of KRAS, ALK, ROS1 and BRAF alterations were not associated with survival (all p > 0.05). Conversely, older age (HR: 1.039; p=0.029), a history of multiple brain irradiation procedures (HR 9.197; p < 0.001) and presence of extracranial metastasis (HR 2.556; p = 0.016) resulted in increased risk of mortality.

Patients requiring surgical resection of an EGFR mutated NSCLC brain metastasis had an associated improved survival compared to patients without this mutation, independent of TKI use. Decreased survival was associated with older age, multiple prior brain radiation therapies and extracranial metastasis 3).


Activating mutations in the epidermal growth factor receptor (EGFR) predict for prolonged progression-free survival in patients with advanced non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy.


A group of patients with non-small cell lung cancer (NSCLC) have tumors that contain an inversion in chromosome 2 that juxtaposes the 5′ end of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the 3′ end of the anaplastic lymphoma kinase (ALK) gene, resulting in the novel fusion oncogene EML4-ALK


Multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed 4).

References

1)

Zer A, Leighl N. Promising targets and current clinical trials in metastatic non-squamous nsclc. Front Oncol. 2014;4:329. doi: 10.3389/fonc.2014.00329.
2)

Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015;4:36–54.
3)

Huang Y, Chow KKH, Aredo JV, Padda SK, Han SS, Kakusa BW, Gephart MH. EGFR mutation status confers survival benefit in non-small cell lung cancer patients undergoing surgical resection of brain metastases: a retrospective cohort study. World Neurosurg. 2019 Jan 30. pii: S1878-8750(19)30210-4. doi: 10.1016/j.wneu.2019.01.112. [Epub ahead of print] PubMed PMID: 30710723.
4)

Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK, Beal K, Amini A, Patil T, Kavanagh BD, Camidge DR, Braunstein SE, Boreta LC, Balasubramanian SK, Ahluwalia MS, Rana NG, Attia A, Gettinger SN, Contessa JN, Yu JB, Chiang VL. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. J Clin Oncol. 2017 Apr 1;35(10):1070-1077. doi: 10.1200/JCO.2016.69.7144. Epub 2017 Jan 23. PubMed PMID: 28113019.

Lumbar spinal stenosis case series

Lumbar spinal stenosis case series

Nine hundred and eighteen patients of the Acıbadem Fulya Hospital and Acıbadem Taksim Hospital were treated for single or multilevel lumbar spinal stenosis (LSS) by bilateral decompression via unilateral approach (BDUA) between January 2002 and January 2016. 180 patients of the 918 underwent microdiscectomy with decompression. They were then followed up postoperatively, at 6 and 12 months with radiological investigations, Oswestry Disability Index (ODI) and 36-item short-form health survey (SF-36) tests.

Four hundred and ninety-two patients were females (53,6%), four hundred and twenty six were males (46,4) whose mean age was 63,83±10,16 (range: 43-79 years). Duration of symptoms ranged from 4 to 49 months. Average follow-up time was 98 months (range 25-168 months) and the reoperation rate (RR) was 2,5%. The ODI scores decreased significantly (30.65± 7.82, to 11.32 ± 2.50 at six months and 11.30 ± 2.49 at first year) and the SF-36 parameter scores demonstrated a significant improvement in the early and late follow-up results.

BDUA for LSS allowed a sufficient and safe decompression of the neural structures, resulted in a highly significant reduction of the symptoms and disability, acceptable RR, and improved health-related quality of life 1).


A successive series of 102 patients with lumbar spinal stenosis from Aachen (with and without previous lumbar surgery) were treated with decompression alone during a 3-year period. Data on pre- and postoperative back pain and leg pain (numerical rating scale [NRS] scale) were retrospectively collected from questionnaires with a return rate of 65% (n = 66). The complete cohort as well as patients with first-time surgery and re-decompression were analyzed separately. Patients were dichotomized to short-term follow-up (< 100 weeks) and long-term follow-up (> 100 weeks) postsurgery.

Overall, both back pain (NRS 4.59 postoperative versus 7.89 preoperative; p < 0.0001) and leg pain (NRS 4.09 versus 6.75; p < 0.0001) improved postoperatively. The short-term follow-up subgroup (50%, n = 33) showed a significant reduction in back pain (NRS 4.0 versus 6.88; p < 0.0001) and leg pain (NRS 2.49 versus 6.91: p < 0.0001). Similar results could be observed for the long-term follow-up subgroup (50%, n = 33) with significantly less back pain (NRS 3.94 versus 7.0; p < 0.0001) and leg pain (visual analog scale 3.14 versus 5.39; p < 0.002) postoperatively. Patients with previous decompression surgery benefit significantly regarding back pain (NRS 4.82 versus 7.65; p < 0.0024), especially in the long-term follow-up subgroup (NRS 4.75 versus 7.67; p < 0.0148). There was also a clear trend in favor of leg pain in patients with previous surgery; however, it was not significant.

Decompression of lumbar spinal stenosis without fusion led to a significant and similar reduction of back pain and leg pain in a short-term and a long-term follow-up group. Patients without previous surgery benefited significantly better, whereas patients with previous decompression benefited regarding back pain, especially for long-term follow-up with a clear trend in favor of leg pain 2).


A total of 25 patients between May 2015 and June 2016 affected by radiologically demonstrated one-level lumbar spinal stenosis (LSS) with facet joint degeneration and grade I spondylolisthesis were included in this prospective study. All the patients underwent laminectomyforaminotomy, and one-level facet fixation (Facet-Link, Inc., Rockaway, New Jersey, United States). Pre- and postoperative clinical (Oswestry Disability Index[ODI], Short Form 36 [SF-36]) and radiologic (radiographs, magnetic resonance imaging, computed tomography) data were collected and analyzed.

Mean follow-up was 12 months. The L4L5 level was involved in 18 patients (72%) and L5S1 in 7 patients (28%); the average operative time was 80 minutes (range: 65-148 minutes), and the mean blood loss was 160 mL (range: 90-200 mL). ODI and SF-36 showed a statistically significant (p < 0.05) improvement at last follow-up.

Transfacet fixation is a safe and effective treatment option in patients with single-level LSS, facet joint degeneration, and mild instability 3).

2017

A retrospective matched-pair cohort study included a total of 144 patients who underwent surgery for bisegmental spinal stenosis at the levels L3-4 and L4-5 between 2008 and 2012. There were 72 matching pairs that corresponded in sex, year of birth, and width of the stenosed segments. The patients’ impairments were reported before, immediately after, and 6 and 12 months after surgery using the Oswestry Disability Questionnaire (ODQ-D) and the EuroQol-5D (EQ-5D). The data were evaluated statistically. Results The comparison of both surgical procedures regarding walking ability (walking a distance with and without a walking aid) revealed a significant difference. Patients who underwent hemilaminectomy had better postoperative results. The individual criteria of the ODQ-D and EQ-5D revealed no significant differences between 2-level fenestration and hemilaminectomy; however, there is always significant postoperative improvement in comparison with preoperative status. Age, sex, body mass index, comorbidities, smoking, and alcohol consumption had no influence on the surgical results. The reoperation rate was between 13% and 15% for both surgical techniques, not being significantly different. Conclusion Fenestration and hemilaminectomy are equivalent therapies for bisegmental lumbar spinal canal stenosis. Regarding walking, the study revealed better results for hemilaminectomy than for fenestration in this cohort of patients. Pain intensity, personal care, lifting and carrying of objects, sitting, social life, and travel all improved significantly postoperatively as compared with preoperatively. In both groups, health status as the decisive predictor improved considerably after surgery. We could show that both surgical methods result in significant postoperative improvement of all the individual criteria of the ODQ-D and the EQ-5D 4).

2016

726 patients with lumbar stenosis (without spondylolisthesis or scoliosis) and a baseline back pain score ≥ 5 of 10 who underwent surgical decompression only. No patient was reported to have significant spondylolisthesis, scoliosis, or sagittal malalignment. Standard demographic and surgical variables were collected, as well as patient outcomes including back and leg pain scores, Oswestry Disability Index (ODI), and EuroQoL 5D (EQ-5D) at baseline and 3 and 12 months postoperatively. RESULTS The mean age of the cohort was 65.6 years, and 407 (56%) patients were male. The mean body mass index was 30.2 kg/m2, and 40% of patients had 2-level decompression, 29% had 3-level decompression, 24% had 1-level decompression, and 6% had 4-level decompression. The mean estimated blood loss was 130 ml. The mean operative time was 100.85 minutes. The vast majority of discharges (88%) were routine home discharges. At 3 and 12 months postoperatively, there were significant improvements from baseline for back pain (7.62 to 3.19 to 3.66), leg pain (7.23 to 2.85 to 3.07), EQ-5D (0.55 to 0.76 to 0.75), and ODI (49.11 to 27.20 to 26.38). CONCLUSIONS Through the 1st postoperative year, patients with lumbar stenosis-without spondylolisthesis, scoliosis, or sagittal malalignment-and clinically significant back pain improved after decompression-only surgery 5).

2015

88 patients with LSS (47 men and 41 women) who ranged in age from 39 to 86 years (mean age 68.7 years). All patients had undergone microendoscopic laminotomy at Osaka City University Graduate School of Medicine from May 2008 through October 2012. The minimum duration of clinical and radiological follow-up was 6 months. All patients were evaluated by Japanese Orthopaedic Association (JOA) and visual analog scale (VAS) scores for low back painleg pain, and leg numbness before and after surgery.

The distance between the C7 plumb line and the posterior corner of the sacrum (sagittal vertical axis [SVA]) was measured on lateral standing radiographs of the entire spine obtained before surgery.

Radiological factors and clinical outcomes were compared between patients with a preoperative SVA ≥ 50 mm (forward-bending trunk [F] group) and patients with a preoperative SVA < 50 mm (control [C] group).

A total of 35 patients were allocated to the F group (19 male and 16 female) and 53 to the C group (28 male and 25 female).

The mean SVA was 81.0 mm for patients in the F group and 22.0 mm for those in the C group. At final follow-up evaluation, no significant differences between the groups were found for the JOA score improvement ratio (73.3% vs 77.1%) or the VAS score for leg numbness (23.6 vs 24.0 mm); the VAS score for low-back pain was significantly higher for those in the F group (21.1 mm) than for those in the C group (11.0 mm); and the VAS score for leg pain tended to be higher for those in the F group (18.9 ± 29.1 mm) than for those in the C group (9.4 ± 16.0 mm).

Preoperative alignment of the spine in the sagittal plane did not affect JOA scores after microendoscopic laminotomy in patients with LSS. However, low-back pain was worse for patients with preoperative anterior translation of the C-7 plumb line than for those without 6).

References

1)

Yüce İ, Kahyaoğlu O, Çavuşoğlu HA, Çavuşoğlu H, Aydın Y. Long term clinical outcome and reoperation rate for microsurgical bilateral decompression via unilateral approach of lumbar spinal stenosis. World Neurosurg. 2019 Jan 30. pii: S1878-8750(19)30203-7. doi: 10.1016/j.wneu.2019.01.105. [Epub ahead of print] PubMed PMID: 30710724.
2)

Geiger MF, Bongartz N, Blume C, Clusmann H, Müller CA. Improvement of Back and Leg Pain after Lumbar Spinal Decompression without Fusion. J Neurol Surg A Cent Eur Neurosurg. 2018 Dec 5. doi: 10.1055/s-0038-1669473. [Epub ahead of print] PubMed PMID: 30517963.
3)

Trungu S, Pietrantonio A, Forcato S, Tropeano MP, Martino L, Raco A. Transfacet Screw Fixation for the Treatment of Lumbar Spinal Stenosis with Mild Instability: A Preliminary Study. J Neurol Surg A Cent Eur Neurosurg. 2018 Sep;79(5):358-364. doi: 10.1055/s-0038-1655760. Epub 2018 Jul 16. PubMed PMID: 30011420.
4)

Schüppel J, Weber F. Retrospective Matched-Pair Cohort Study on Effect of Bisegmental Fenestration versus Hemilaminectomy for Bisegmental Spinal Canal Stenosis at L3-L4 and L4-L5. J Neurol Surg A Cent Eur Neurosurg. 2017 Jan 9. doi: 10.1055/s-0036-1597617. [Epub ahead of print] PubMed PMID: 28068753.
5)

Crawford CH 3rd, Glassman SD, Mummaneni PV, Knightly JJ, Asher AL. Back pain improvement after decompression without fusion or stabilization in patients with lumbar spinal stenosis and clinically significant preoperative back pain. J Neurosurg Spine. 2016 Nov;25(5):596-601. PubMed PMID: 27285666.
6)

Dohzono S, Toyoda H, Matsumoto T, Suzuki A, Terai H, Nakamura H. The influence of preoperative spinal sagittal balance on clinical outcomes after microendoscopic laminotomy in patients with lumbar spinal canal stenosis. J Neurosurg Spine. 2015 Jul;23(1):49-54. doi: 10.3171/2014.11.SPINE14452. Epub 2015 Apr 3. PubMed PMID: 25840041.
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