Faculty Bibliography

Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.

Background: Autologous stem cell transplant (ASCT) remains standard of care for eligible newly diagnosed myeloma patients (TE NDMM). Induction prior to ASCT frequently includes lenalidomide, reported to have an adverse effect on peripheal blood stem cell (PBSC) harvest in some studies.
Aim(s): The UK NCRI Myeloma XI/+ study compared induction combinations including thalidomide or lenalidomide giving the opportunity to compare PBSC harvests between patients treated with different immunomodulatory agents.
Method(s): TE NDMM patients were randomised to triplet combinations, thalidomide or lenalidomide plus dexamethasone and cyclophosphamide (Tdc/Rdc) or the quadruplet combination carfilzomib+Rdc (KRdc). Induction was given for a min. of 4 cycles but continued to max. response. Patients who received Tdc/Rdc and achieved a max. response less than VGPR underwent response-adapted intensification therapy. PBSC harvest was planned to occur after the completion of induction+/- intensification. Stem cell mobilisation and harvest was performed according to local practice with advice to aim for the collection of sufficient cells for at least two transplants. The median number of CD34+ cells harvested was compared between patients randomised to Tdc, Rdc and KRdc and those who received 4, 5-6 or >6 cycles of induction. Mann-Whitney U Tests were used to compare groups. Only patients achieving >=VGPR to initial induction, completing >=4 cycles and proceeding directly to ASCT were included in this analysis to avoid any impact of response or intensification therapy on harvest outcome.
Result(s): Of the1543 patients included, 521 had received Tdc (51.0% of all patients randomised to Tdc), 610 Rdc (59.7%), 412 KRdc (78.3%). Of these patients 88.4% underwent harvest (Tdc 86.9%, Rdc 87.5%, KRdc 91.5%). The median number of CD34+ cells harvested was lower for those who had received lenalidomide compared to thalidomide. Patients who received Tdc harvested a median 4.6x10^6/kg CD34+ cells, Rdc 4.1, KRdc 4.2 (Rdc vs Tdc p=0.0002, KRdc vs Rdc p=0.1766, KRdc vs Tdc p=0.0210). There was also a reduction in the median CD34+ cells harvested for patients requiring >6 cycles of induction to achieve maximum response prior to harvest. 4 cycles 4.5 x10^6/kg CD34+ cells, 5-6 cycles 4.2, >6 cycles 4.1 (4 vs 5-6 p=0.1212, 5-6 vs >6 p=0.1839, 4 vs >6 p=0.0262). The reduction in CD34+ cells with increasing number of induction cycles appeared greater for those patients who received lenalidomide induction. Tdc: 4 cycles 4.9 x10^6/kg CD34+ cells, 5-6 cycles 4.6, >6 cycles 4.6. Rdc: 4 cycles 4.4, 5-6 cycles 4.0, >6 cycles 3.5. KRdc: 4 cycles 4.4, 5-6 cycles 4.1, >6 cycles 3.9. This corresponded to a reduction in the proportion of patients meeting the threshold for two ASCTs both between therapies and with increasing cycles. Tdc: 4 cycles 63.0%, 5-6 cycles 60.2%, >6 cycles 61.4%. Rdc: 4 cycles 54.3%, 5-6 cycles 47.4%, >6 cycles 46.2%. KRdc: 4 cycles 60.9%, 5-6 cycles 49.3%, >6 cycles 41.7%. Despite these differences, more than 96% of patients in all groups were considered to have enough stem cells and proceeded to first ASCT within the trial, with no differences between treatment groups. Summary/Conclusion: Lenalidomide-based induction therapy was associated with lower median CD34+ cells harvested than thalidomide-based induction. This had no impact on the proportion of patients able to undergo first ASCT. The reduction in median CD34+ cells with lenalidomide was most marked when >4 cycles were administered. This should be considered when planning the timing of harvests, especially if storage of sufficient cells for two ASCTs is desired

BACKGROUND:Thoracic and lumbar burst fractures in neurologically intact patients are considered to be inherently stable, and responsive to nonsurgical management. There is a lack of consensus regarding the optimal conservative treatment modality. The question remains whether external bracing is necessary vs mobilization without a brace after these injuries. OBJECTIVE:To determine if the use of external bracing improves outcomes compared to no brace for neurologically intact patients with thoracic or lumbar burst fractures. METHODS:A systematic review of the literature was performed using the National Library of Medicine PubMed database and the Cochrane Library for studies relevant to thoracolumbar trauma. Clinical studies specifically comparing external bracing to no brace for neurologically intact patients with thoracic or lumbar burst fractures were selected for review. RESULTS:Three studies out of 1137 met inclusion criteria for review. One randomized controlled trial (level I) and an additional randomized controlled pilot study (level II) provided evidence that both external bracing and no brace equally improve pain and disability in neurologically intact patients with burst fractures. There was no difference in final clinical and radiographic outcomes between patients treated with an external brace vs no brace. One additional level IV retrospective study demonstrated equivalent clinical outcomes for external bracing vs no brace. CONCLUSION:This evidence-based guideline provides a grade B recommendation that management either with or without an external brace is an option given equivalent improvement in outcomes for neurologically intact patients with thoracic and lumbar burst fractures. The decision to use an external brace is at the discretion of the treating physician, as bracing is not associated with increased adverse events compared to no brace. QUESTION:Does the use of external bracing improve outcomes in the nonoperative treatment of neurologically intact patients with thoracic and lumbar burst fractures? RECOMMENDATION:The decision to use an external brace is at the discretion of the treating physician, as the nonoperative management of neurologically intact patients with thoracic and lumbar burst fractures either with or without an external brace produces equivalent improvement in outcomes. Bracing is not associated with increased adverse events compared to not bracing. Strength of Recommendation: Grade B The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_8.

BACKGROUND:Treatment of thoracolumbar burst fractures has traditionally involved spinal instrumentation with fusion performed with standard open surgical techniques. Novel surgical strategies, including instrumentation without fusion and percutaneous instrumentation alone, have been considered less invasive and more efficient treatments. OBJECTIVE:To review the current literature and determine the role of fusion in instrumented fixation, as well as the role of percutaneous instrumentation, in the treatment of patients with thoracolumbar burst fractures. METHODS:The task force members identified search terms/parameters and a medical librarian implemented the literature search, consistent with the literature search protocol (see Appendix I), using the National Library of Medicine PubMed database and the Cochrane Library for the period from January 1, 1946 to March 31, 2015. RESULTS:A total of 906 articles were identified and 38 were selected for full-text review. Of these articles, 12 articles met criteria for inclusion in this systematic review. CONCLUSION:There is grade A evidence for the omission of fusion in instrumented fixation for thoracolumbar burst fractures. There is grade B evidence that percutaneous instrumentation is as effective as open instrumentation for thoracolumbar burst fractures. QUESTION:Does the addition of arthrodesis to instrumented fixation improve outcomes in patients with thoracic and lumbar burst fractures? RECOMMENDATION:It is recommended that in the surgical treatment of patients with thoracolumbar burst fractures, surgeons should understand that the addition of arthrodesis to instrumented stabilization has not been shown to impact clinical or radiological outcomes, and adds to increased blood loss and operative time. Strength of Recommendation: Grade A. QUESTION:How does the use of minimally invasive techniques (including percutaneous instrumentation) affect outcomes in patients undergoing surgery for thoracic and lumbar fractures compared to conventional open techniques? RECOMMENDATION:Stabilization using both open and percutaneous pedicle screws may be considered in the treatment of thoracolumbar burst fractures as the evidence suggests equivalent clinical outcomes. Strength of Recommendation: Grade B The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_12.

QUESTION:Does the active maintenance of arterial blood pressure after injury affect clinical outcomes in patients with thoracic and lumbar fractures? RECOMMENDATIONS:There is insufficient evidence to recommend for or against the use of active maintenance of arterial blood pressure after thoracolumbar spinal cord injury. Grade of Recommendation: Grade Insufficient However, in light of published data from pooled (cervical and thoracolumbar) spinal cord injury patient populations, clinicians may choose to maintain mean arterial blood pressures >85 mm Hg in an attempt to improve neurological outcomes. Consensus Statement by the Workgroup The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_6.

QUESTION:Does the administration of a specific pharmacologic agent (eg, methylprednisolone) improve clinical outcomes in patients with thoracic and lumbar fractures and spinal cord injury? RECOMMENDATION:There is insufficient evidence to make a recommendation; however, the task force concluded, in light of previously published data and guidelines, that the complication profile should be carefully considered when deciding on the administration of methylprednisolone. Strength of recommendation: Grade Insufficient The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_5.

BACKGROUND:The thoracic and lumbar ("thoracolumbar") spine are the most commonly injured region of the spine in blunt trauma. Trauma of the thoracolumbar spine is frequently associated with spinal cord injury and other visceral and bony injuries. Prolonged pain and disability after thoracolumbar trauma present a significant burden on patients and society. OBJECTIVE:To formulate evidence-based clinical practice recommendations for the care of patients with injuries to the thoracolumbar spine. METHODS:A systematic review of the literature was performed using the National Library of Medicine PubMed database and the Cochrane Library for studies relevant to thoracolumbar spinal injuries based on specific clinically oriented questions. Relevant publications were selected for review. RESULTS:For all of the questions posed, the literature search yielded a total of 6561 abstracts. The task force selected 804 articles for full text review, and 78 were selected for inclusion in this overall systematic review. CONCLUSION:The available evidence for the evaluation and treatment of patients with thoracolumbar spine injuries demonstrates considerable heterogeneity and highly variable degrees of quality. However, the workgroup was able to formulate a number of key recommendations to guide clinical practice. Further research is needed to counter the relative paucity of evidence that specifically pertains to patients with only thoracolumbar spine injuries. The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_1.

QUESTION 1:Are there classification systems for fractures of the thoracolumbar spine that have been shown to be internally valid and reliable (ie, do these instruments provide consistent information between different care providers)? RECOMMENDATION 1:A classification scheme that uses readily available clinical data (eg, computed tomography scans with or without magnetic resonance imaging) to convey injury morphology, such as Thoracolumbar Injury Classification and Severity Scale or the AO Spine Thoracolumbar Spine Injury Classification System, should be used to improve characterization of traumatic thoracolumbar injuries and communication among treating physicians. Strength of Recommendation: Grade B. QUESTION 2:In treating patients with thoracolumbar fractures, does employing a formally tested classification system for treatment decision-making affect clinical outcomes? RECOMMENDATION 2:There is insufficient evidence to recommend a universal classification system or severity score that will readily guide treatment of all injury types and thereby affect outcomes. Strength of Recommendation: Grade Insufficient The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_2.

QUESTION:Does the choice of surgical approach (anterior, posterior, or combined anterior-posterior) improve clinical outcomes in patients with thoracic and lumbar fractures? RECOMMENDATIONS:In the surgical treatment of patients with thoracolumbar burst fractures, physicians may use an anterior, posterior, or a combined approach as the selection of approach does not appear to impact clinical or neurological outcomes. Strength of Recommendation: Grade B With regard to radiologic outcomes in the surgical treatment of patients with thoracolumbar fractures, physicians may utilize an anterior, posterior, or combined approach because there is conflicting evidence in the comparison among approaches. Strength of Recommendation: Grade Insufficient With regard to complications in the surgical treatment of patients with thoracolumbar fractures, physicians may use an anterior, posterior, or combined approach because there is conflicting evidence in the comparison among approaches. Strength of Recommendation: Grade Insufficient The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_11.