Interhemispheric Transcallosal Resection of Large Colloid Cyst Through Nondilated Foramen with Use of Microblade Retractor: 2-Dimensional Operative Video.

Patients who present with a large colloid cyst (CC) and nondilated ventricles represent a therapeutic challenge.1-3 Although transcallosal approaches provide reliable access to the lateral ventricle and foramen of Monro, direct visualization of the vascular attachment of the CC to the roof of the third ventricle is not always possible. This can be especially true with CCs located more posteriorly and superiorly.4 Opening of the choroidal fissure can improve access and visualization to the posterior third ventricle; however, this maneuver is associated with some element of risk.5 There is a paucity of operative video in the literature illustrating the technique of gentle, microblade elevation of the fornix to improve visualization into the third ventricle and, on occasion, avoid the need to open the choroidal fissure.6 We report the case of a 28-year-old woman who presented with headaches and progressive short-term memory dysfunction (Video 1). Magnetic resonance imaging demonstrated a 17-mm CC associated with distortion and thinning of the bilateral fornices without hydrocephalus. The patient was offered interhemispheric, transcallosal resection. Intraoperatively, gentle elevation of the fornix with a microblade retractor facilitated access to the vascular attachment of the colloid cyst-obviating the need to open the choroidal fissure. The index operative video discusses the technical nuances associated with trans-callosal resection of CC with use of the microblade retractor. Special emphasis is placed on the intricate relationship of neighboring anatomic structures. The patient consented to the procedure and the publication of her image.

Synthetic Interbody Devices and Traditional Bone Graft Are Associated With a Similar Rate of Surgical Complications After 1-2 Level Anterior Cervical Discectomy and Fusions.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To compare the rates of all-cause surgical complications of synthetic interbody devices versus allograft or autograft in patients undergoing 1-2 levels anterior cervical discectomy and fusion (ACDF) procedures. SUMMARY OF BACKGROUND DATA: Cervical degenerative disorders affect up to 60% of older adults in the United States. Both traditional allograft or autograft and synthetic interbody devices (polyetheretherketone or titanium) are used for decompression and arthrodesis, with increasing utilization of the latter. However, the differences in their postsurgical complication profiles are not well-characterized. PATIENTS AND METHODS: Patients who underwent 1-2 level ACDFs for cervical radiculopathy or myelopathy between 2010 and 2022 were identified using the PearlDiver Mariner all-claims insurance database. Patients undergoing surgery for nondegenerative pathologies, such as tumors, trauma, or infection, were excluded. 1:1 exact matching was performed based on factors that were significant predictors of all-cause surgical complications in a linear regression model. The primary outcome measure was the development of all-cause surgical complications after 1-2 level ACDFs. The secondary outcome was all-cause medical complications. RESULTS: 1:1 exact matching resulted in two equal groups of 11,430 patients who received treatment with synthetic interbody devices or allograft/autograft. No statistically significant difference in all-cause surgical complications was found between the synthetic cohort and the allograft or autograft cohort after 1-2 level ACDFs (Relative Risk: 0.86, 95% confidence interval: 0.730-1.014, P = 0.079). No significant differences were observed regarding any specific surgical complications except for pseudoarthrosis (Relative Risk: 0.73, 95% confidence interval: 0.554-0.974, P = 0.037), which was higher in the allograft/autograft cohort. CONCLUSION: After 1:1 exact matching to control for confounding variables, the findings of this study suggest that all-cause surgical complications are similar in patients undergoing ACDFs with synthetic interbody devices or allograft/autographs. However, the rate of pseudarthrosis appears to be higher in patients with allograft/autographs. Future prospective studies are needed to corroborate these findings.

Cannabis Use is Associated With Higher Rates of Pseudarthrosis Following TLIF: A Multi-Institutional Matched-Cohort Study.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: To compare the rates of pseudarthrosis in patients undergoing 1 to 3 level transforaminal lumbar interbody fusion (TLIF) procedures between cannabis users and noncannabis users. SUMMARY OF BACKGROUND DATA: Recreational use of cannabis is common, though it remains poorly studied and legally ambiguous in the United States. Patients with back pain may turn to adjunctive use of cannabis to manage their pain. However, the implications of cannabis use on the achievement of bony fusion are not well-characterized. METHODS: Patients who underwent 1 to 3 level TLIF for degenerative disc disease or degenerative spondylolisthesis between 2010 and 2022 were identified using the PearlDiver Mariner all-claims insurance database. Cannabis users were identified with ICD 10 code F12.90. Patients undergoing surgery for nondegenerative pathologies such as tumors, trauma, or infection were excluded. 1:1 exact matching was performed using demographic factors, medical comorbidities, and surgical factors which were significantly associated with pseudarthrosis in a linear regression model. The primary outcome measure was development of pseudarthrosis within 24 months after 1 to 3 level TLIF. The secondary outcomes were the development of all-cause surgical complications as well as all-cause medical complications. RESULTS: A 1:1 exact matching resulted in two equal groups of 1593 patients who did or did not use cannabis and underwent 1 to 3 level TLIF. Patients who used cannabis were 80% more likely to experience pseudarthrosis compared with patients who do not [relative risk (RR): 1.816, 95% CI: 1.291-2.556, P <0.001]. Similarly, cannabis use was associated with significantly higher rates of all-cause surgical complications (RR: 2.350, 95% CI: 1.399-3.947, P =0.001) and all-cause medical complications (RR: 1.934, 95% CI: 1.516-2.467, P <0.001). CONCLUSION: After 1:1 exact matching to control for confounding variables, the findings of this study suggest that cannabis use is associated with higher rates of pseudarthrosis, as well as higher rates of all-cause surgical and all-cause medical complications. Further studies are needed to corroborate our findings.

Correlation Between Rod Fracture and Shear Stress: A Novel Parameter.

BACKGROUND: We sought to assess the accuracy of a novel parameter proportional to the rod shear stress (RSS) in identifying patients at risk of rod fracture (RF) after surgery for correction of adult spinal deformity. METHODS: We performed a retrospective medical record review of patients aged ≥18 years treated for adult spinal deformity between 2004 and 2014 with ≥24 months of follow-up. The primary outcome was RFs identified radiographically. Patient weight (w), number of instrumented levels (N), and minimum rod diameter (d) were recorded and used to calculate the RSS parameter (RSS=Nwd2). Receiver operating characteristic curves were produced and the area under the curve (AUC ± 95% confidence interval [CI]) was calculated to compare this parameter's discriminative accuracy to that of its constituent variables. The sensitivity, specificity, and likelihood ratios (LRs) were calculated. RESULTS: A total of 28 RF-positive and 154 RF-negative patients were included. The average age was 59.2 ± 9.6 years, and 93.4% were women. The RSS parameter produced the greatest AUC (0.73 ± 0.11). At an RSS cutoff of 30.1, it achieved a sensitivity of 71.4% and specificity of 71.4% (LR, 2.5; 95% CI, 1.8-3.5). The number of instrumented levels produced the next-greatest AUC (0.65 ± 0.12), with a sensitivity of 78.6% and specificity of 50.0% at a cutoff of 15 (LR, 1.6; 95% CI, 1.2-2.0). CONCLUSIONS: The RSS is calculated using easily obtainable information and shows potential as a tool for predicting patient-specific risk of RF after spinal fusion. The number of instrumented levels also correlates strongly with the occurrence of RFs and is not significantly less accurate than the RSS. A larger sample size and prospective validation would be useful in determining with greater confidence which parameter is superior for predicting RFs after spinal fusion.

No Difference in Surgical Outcomes between Stand-Alone Devices and Anterior Plating for 1-2 level Anterior Cervical Discectomy and Fusion: A 1:1 Exact Matched Analysis.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: Compare rates of all-cause surgical and medical complications between zero-profile (stand-alone) implants versus any graft type with anterior plate in patients undergoing 1-2 level anterior cervical discectomy and fusion (ACDF) for treatment of degenerative cervical myeloradiculopathy. SUMMARY OF BACKGROUND DATA: Degenerative cervical myeloradiculopathy is increasingly prevalent in older adults. ACDF is a common surgical procedure for decompression of neural structures and stabilization and has been shown to have excellent outcomes. While ACDFs performed with a graft and plate has been the gold standard, more recently, zero-profile implants were developed to decrease implant related complications, such as severe postoperative dysphagia. However, there is a paucity of papers comparing the surgical and medical complications profile of zero-profile (stand-alone) implants to grafts with plating systems. METHODS: Data was extracted from the PearlDiver Mariner Database using CPT codes to classify patients into 1-level, 2-levels, and total 1-2 level ACDFs. Patients undergoing surgery for non-degenerative pathologies such as tumors, trauma, or infection were excluded. RESULTS: 1:1 exact matching created two equal groups of 7,284 patients that underwent 1-2 level ACDF with either grafting with a plate or zero-profile (standalone) implant. There were no statistically significant difference in all-cause surgical complications, pseudarthrosis rate, dysphagia or need for revision surgery between both cohorts (RR 0.99, 95% CI 0.80-1.21, P = 0.95). Additionally, all-cause medical complications were similar between both cohorts (RR 1.07, 95% CI 0.862-1.330, P = 0.573) or any specific surgical or medical complication included in this study. CONCLUSION: After 1:1 exact matching, the results of this study suggest that zero-profile (stand-alone) implants have similar outcomes compared to grafts with plating systems, with no observed differences in all-cause surgical or medical complications profile.

Surgeon Experience Matters: An Exact Matched Analysis of TLIF Outcomes Demonstrates No Difference in Surgical Outcomes Between Experienced Neurosurgeons and Orthopedic Surgeons.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To compare surgical and medical complications profile between neurosurgeons and orthopedic surgeons after transforaminal lumbar interbody fusion (TLIF) procedures. BACKGROUND: Studies comparing the impact of spine surgeon specialty (neurosurgery vs. orthopedic spine) on TLIF outcomes have been inconclusive and failed to control for operative learning curves and surgical maturity. Orthopedic spine surgeons perform fewer spine procedures in residency, although these differences may be attenuated by mandatory fellowship before starting practice. Any observed differences are likely attenuated with increasing surgeon experience. MATERIALS AND METHODS: Using an all-payer claims database, PearlDiver Mariner, 120 million patient records were analyzed between 2010 and 2022, to identify individuals with lumbar stenosis or spondylolisthesis who underwent index one- to three-level TLIF procedures. International Classification of Diseases-Ninth Edition (ICD-9), International Classification of Diseases-10th Edition (ICD-10) and Current Procedural Terminology (CPT) codes were used to query the database. Only Neurosurgeons and Orthopedic spine surgeons who had performed at least 250 procedures were included in the study. Patients undergoing surgery for tumor, trauma, or infection were excluded. 1:1 exact matching was performed using demographic factors, medical comorbidities, and surgical factors which were significantly associated with all-cause surgical or medical complications in a linear regression model. RESULTS: 1:1 exact matching created two equal groups of 18,195 patients without baseline differences who underwent TLIF procedures by neurosurgeons or orthopedic surgeons. There was no difference in all-cause surgical complications between neurosurgeons and orthopedic spine surgeons (relative risk=1.008, 95% CI: 0.850-1.195, P =0.965). All-cause medical complication rate was higher in the neurosurgery cohort (relative risk=1.144, 95% CI: 1.042-1.258, P =0.005). CONCLUSION: The results of this study suggest that after accounting for surgical maturity, neurosurgeons and orthopedic spine surgeons have similar surgical outcomes. However, neurosurgeons have higher all-cause medical complication rates compared with orthopedic spine surgeons. Further research is warranted to validate this relationship in other spine procedures and for other outcomes.

TLIF is Associated With Lower Rates of Adjacent Segment Disease and Complications Compared to ALIF: A Matched-Cohort Analysis.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To compare the rate of adjacent segment disease (ASD) in patients undergoing anterior lumbar interbody fusion (ALIF) versus transforaminal lumbar interbody fusion (TLIF) for the treatment of degenerative stenosis and spondylolisthesis. SUMMARY OF BACKGROUND DATA: ALIF and TLIF are frequently used to treat Lumbar stenosis and spondylolisthesis. While both approaches have distinct advantages, it is unclear whether there are any differences in rates of ASD and postoperative complications. METHODS: A retrospective cohort study of patients who underwent index 1-3 levels ALIF or TLIF between 2010 and 2022, using the PearlDiver Mariner Database, an all-claims insurance database (120 million patients). Patients with a history of prior lumbar surgery and those undergoing surgery for cancer, trauma, or infection were excluded. Exact 1:1 matching was performed using demographic factors, medical comorbidities, and surgical factors found to be significantly associated with ASD in a linear regression model. The primary outcome was a new diagnosis of ASD within 36 months of index surgery, and secondary outcomes were all-cause medical and surgical complications. RESULTS: Exact 1:1 matching resulted in 2 equal groups of 106,451 patients undergoing TLIF and ALIF. The TLIF approach was associated with a lower risk of ASD (RR 0.58, 95% CI 0.56-0.59, P < 0.001) and all-cause medical complications (RR 0.94, 95% CI 0.91-0.98, P =0.002). All-cause surgical complications were not significantly different between both groups. CONCLUSION: After 1:1 exact matching to control for confounding variables, this study suggests that for patients with symptomatic degenerative stenosis and spondylolisthesis, a TLIF procedure (compared to ALIF) is associated with a decreased risk of developing ASD within 36 months of index surgery. Future prospective studies are needed to corroborate these findings. LEVEL OF EVIDENCE: Level-3.

Anterior occipital condyle screw placement through the endonasal corridor: proof of concept study with cadaveric analysis.

PURPOSE: Odontoidectomy for ventral compressive pathology may result in O-C1 and/or C1-2 instability. Same-stage endonasal C1-2 spinal fusion has been advocated to eliminate risks associated with separate-stage posterior approaches. While endonasal methods for C1 instrumentation and C1-2 trans-articular stabilization exist, no hypothetical construct for endonasal occipital instrumentation has been validated. We provide an anatomic description of anterior occipital condyle (AOC) screw endonasal placement as proof-of-concept for endonasal craniocervical stabilization. METHODS: Eight adult, injected cadaveric heads were studied for placing 16 AOC screws endonasally. Thin-cut CT was used for registration. After turning a standard inferior U-shaped nasopharyngeal flap endonasally, 4 mm × 22 mm AOC screws were placed with a 0° driver using neuronavigation. Post-placement CT scans were obtained to determine: site-of-entry, measured from the endonasal projection of the medial O-C1 joint; screw angulation in sagittal and axial planes, proximity to critical structures. RESULTS: Average site-of-entry was 6.88 mm lateral and 9.74 mm rostral to the medial O-C1 joint. Average angulation in the sagittal plane was 0.16° inferior to the palatal line. Average angulation in the axial plane was 23.97° lateral to midline. Average minimum screw distances from the jugular bulb and hypoglossal canal were 4.80 mm and 1.55 mm. CONCLUSION: Endonasal placement of AOC screws is feasible using a 0° driver. Our measurements provide useful parameters to guide optimal placement. Given proximity of hypoglossal canal and jugular bulb, neuronavigation is recommended. Biomechanical studies will ultimately be necessary to evaluate the strength of AOC screws with plate-screw constructs utilizing endonasal C1 lateral mass or C1-2 trans-articular screws as inferior fixation points.

Posterior Quadrant Disconnection Procedure for Intractable Epilepsy: A Case Series of 5 Young Pediatric Patients.

BACKGROUND: Posterior quadrant disconnection (PQD) has been described as a treatment for patients with refractory posterior quadrant subhemispheric epilepsy. Surgical outcomes are difficult to interpret because of limited literature. OBJECTIVE: To provide insight regarding the operative technique and postsurgical seizure freedom in young pediatric patients who underwent surgical disconnection for the treatment of posterior quadrant subhemispheric epilepsy at our institution. METHODS: The authors retrospectively analyzed a series of 5 patients who underwent PQD between 2019 and 2021. Charts were reviewed for preoperative workup including noninvasive/invasive testing, operative reports, and postoperative follow-up data which included degree of seizure freedom, completion of disconnection, and complications. RESULTS: Five patients were included in this series. The median age at seizure onset was 12 months (range 3-24 months), and the median age at surgery was 36 months (range 22-72 months). Histopathology confirmed focal cortical dysplasia in 3 of 5 patients (2 patients with type IB; 1 with type IIID). The average length of follow-up after surgery was 16.8 months (range 12-24 months). All patients underwent complete disconnection of the posterior quadrant without complications. Four of 5 patients (80%) had Engel score of I, while the remaining patient had an Engel score of IIB. CONCLUSION: Our early results demonstrate that complete PQD can be successful at providing excellent seizure freedom and functional outcomes in carefully selected young pediatric patients who have concordant seizure semiology, noninvasive/invasive testing, and imaging findings with primary seizure onset zone within the ipsilateral posterior quadrant. Meticulous surgical planning and thorough understanding of the surgical anatomy and technique are critical to achieving complete disconnection.

Diet-Induced Obesity Impairs Outcomes and Induces Multi-Factorial Deficiencies in Effector T Cell Responses Following Anti-CTLA-4 Combinatorial Immunotherapy in Renal Tumor-Bearing Mice.

Associations between modifiable factors and the efficacy of cancer immunotherapies remain uncertain. We found previously that diet-induced obesity (DIO) reduces the efficacy of an immunotherapy consisting of adenovirus-encoded TRAIL plus CpG oligonucleotide (AdT/CpG) in mice with renal tumors. To eliminate confounding effects of diet and determine whether outcomes could be improved in DIO mice, we evaluated AdT/CpG combined with anti-CTLA-4 in diet-matched, obese-resistant (OB-RES) versus DIO tumor-bearing mice. Therapy-treated OB-RES mice displayed effective renal tumor control and sustained CD4+ and CD8+ T cell responses. In contrast, therapy-treated DIO mice exhibited progressive tumor outgrowth and blunted T cell responses, characterized by reduced intratumoral frequencies of IFNγ+ CD4+ and CD8+ T cells. Weak effector T cell responses in therapy-treated DIO mice were accompanied by low intratumoral concentrations of the T cell chemoattractant CCL5, heightened concentrations of pro-tumorigenic GM-CSF, and impaired proliferative capacity of CD44+CD8+ T cells in tumor-draining lymph nodes. Our findings demonstrate that in lean mice with renal tumors, combining in situ T cell priming upstream of anti-CTLA-4 enhances outcomes versus anti-CTLA-4 alone. However, host obesity is associated with heightened immunotherapy resistance, characterized by multi-factorial deficiencies in effector CD4+ and CD8+ T cell responses that extend beyond the tumor microenvironment.

Obesity-Associated Myeloid-Derived Suppressor Cells Promote Apoptosis of Tumor-Infiltrating CD8 T Cells and Immunotherapy Resistance in Breast Cancer.

Nearly 70% of adults in the US are currently overweight or obese. Despite such high prevalence, the impact of obesity on antitumor immunity and immunotherapy outcomes remains incompletely understood, particularly in patients with breast cancer. Here, we addressed these gaps in knowledge using two murine models of breast cancer combined with diet-induced obesity. We report that obesity increases CXCL1 concentrations in the mammary tumor microenvironment, driving CXCR2-mediated chemotaxis and accumulation of granulocytic myeloid-derived suppressor cells (G-MDSCs) expressing Fas ligand (FasL). Obesity simultaneously promotes hyperactivation of CD8 tumor-infiltrating lymphocytes (TILs), as evidenced by increased expression of CD44, PD-1, Ki-67, IFNγ, and the death receptor Fas. Accordingly, G-MDSCs induce Fas/FasL-mediated apoptosis of CD8 T cells ex vivo and in vivo. These changes promote immunotherapy resistance in obese mice. Disruption of CXCR2-mediated G-MDSC chemotaxis in obese mice is sufficient to limit intratumoral G-MDSC accumulation and improve immunotherapy outcomes. The translational relevance of our findings is demonstrated by transcriptomic analyses of human breast tumor tissues, which reveal positive associations between CXCL1 expression and body mass index, poor survival, and a MDSC gene signature. Further, this MDSC gene signature is positively associated with FASLG expression. Thus, we have identified a pathway wherein obesity leads to increased intratumoral CXCL1 concentrations, which promotes CXCR2-mediated accumulation of FasL+ G-MDSCs, resulting in heightened CD8 TIL apoptosis and immunotherapy resistance. Disruption of this pathway may improve immunotherapy outcomes in patients with breast cancer and obesity.

The Antidiabetic Agent Acarbose Improves Anti-PD-1 and Rapamycin Efficacy in Preclinical Renal Cancer.

Although immune checkpoint inhibitors and targeted therapeutics have changed the landscape of treatment for renal cell carcinoma (RCC), most patients do not experience significant clinical benefits. Emerging preclinical studies report that nutrition-based interventions and glucose-regulating agents can improve therapeutic efficacy. However, the impact of such agents on therapeutic efficacy in metastatic kidney cancer remains unclear. Here, we examined acarbose, an alpha-glucosidase inhibitor and antidiabetic agent, in a preclinical model of metastatic kidney cancer. We found that acarbose blunted postprandial blood glucose elevations in lean, nondiabetic mice and impeded the growth of orthotopic renal tumors, an outcome that was reversed by exogenous glucose administration. Delayed renal tumor outgrowth in mice on acarbose occurred in a CD8 T cell-dependent manner. Tumors from these mice exhibited increased frequencies of CD8 T cells that retained production of IFNγ, TNFα, perforin, and granzyme B. Combining acarbose with either anti-PD-1 or the mammalian target of rapamycin inhibitor, rapamycin, significantly reduced lung metastases relative to control mice on the same therapies. Our findings in mice suggest that combining acarbose with current RCC therapeutics may improve outcomes, warranting further study to determine whether acarbose can achieve similar responses in advanced RCC patients in a safe and likely cost-effective manner.

Therapeutic Time-restricted Feeding Reduces Renal Tumor Bioluminescence in Mice but Fails to Improve Anti-CTLA-4 Efficacy.

BACKGROUND/AIM: Dietary interventions like time-restricted feeding (TRF) show promising anti-cancer properties. We examined whether therapeutic TRF alone or combined with immunotherapy would diminish renal tumor growth in mice of varying body weights. MATERIALS AND METHODS: Young (7 week) chow-fed or older (27 week) high-fat diet (HFD)-fed BALB/c mice were orthotopically injected with renal tumor cells expressing luciferase. After tumor establishment, mice were randomized to ad libitum feeding or TRF +/- anti-CTLA-4. Body composition, tumor viability and growth, and immune responses were quantified. RESULTS: TRF alone reduced renal tumor bioluminescence in older HFD-fed, but not young chow-fed mice. In the latter, TRF mitigated tumor-induced loss of lean- and fat-mass. However, TRF did not alter excised renal tumor weights or intratumoral immune responses and failed to improve anti-CTLA-4 outcomes in any mice. CONCLUSION: Therapeutic TRF exhibits modest anti-cancer properties but fails to improve anti-CTLA-4 immune checkpoint blockade in murine renal cancer.

Obesity induces limited changes to systemic and local immune profiles in treatment-naive human clear cell renal cell carcinoma.

Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1ß, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.

Obesity diminishes response to PD-1-based immunotherapies in renal cancer.

BACKGROUND: Obesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes. METHODS: We investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, 'BMI' ≥30 kg/m2) or non-obese (BMI <30 kg/m2) undergoing partial or full nephrectomy (n=19) then used to evaluate the frequency and phenotype of intratumoral CD8+ T cells, including PD-1 status, by flow cytometry. In mice, antitumor immunity and excised renal tumor weights were evaluated ±administration of a combinatorial anti-PD-1 therapy. For a subset of murine renal tumors, immunophenotyping was performed by flow cytometry and immunogenetic profiles were evaluated via nanoString. RESULTS: With obesity, RCC patients receiving anti-PD-1 administration exhibited shorter PFS (p=0.0448) and OS (p=0.0288). Treatment-naive renal cancer subjects had decreased frequencies of tumor-infiltrating PD-1highCD8+ T cells, a finding recapitulated in our murine model. Following anti-PD-1-based immunotherapy, both lean and obese mice possessed distinct populations of treatment responders versus non-responders; however, obesity reduced the frequency of treatment responders (73% lean vs 44% obese). Tumors from lean and obese treatment responders displayed similar immunogenetic profiles, robust infiltration by PD-1int interferon (IFN)γ+CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC), yielding favorable CD44+CD8+ T cell to MDSC ratios. Neutralizing interleukin (IL)-1ß in obese mice improved treatment response rates to 58% and reduced MDSC accumulation in tumors. CONCLUSIONS: We find that obesity is associated with diminished efficacy of anti-PD-1-based therapies in renal cancer, due in part to increased inflammatory IL-1ß levels, highlighting the need for continued study of this critical issue.

Randomized trial of weight loss in primary breast cancer: Impact on body composition, circulating biomarkers and tumor characteristics.

Obesity adversely impacts overall and cancer-specific survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, feasibility and effects in patients are unknown. A two-arm, single-blinded, randomized controlled weight-loss trial was undertaken presurgery among 32 overweight/obese, Stage 0-II breast cancer patients. The attention control arm (AC) received basic nutritional counseling and upper-body progressive resistance training whereas the weight loss intervention (WLI) arm received identical guidance, plus counseling on caloric restriction and aerobic exercise to promote 0.68-0.92 kg/week weight loss. Anthropometrics, body composition, blood and survey data were collected at baseline and presurgery ∼30 days later. Tumor markers (e.g., Ki67) and gene expression were assessed on biopsy and surgical specimens; sera were analyzed for cytokines, growth and metabolic factors. Significant WLI vs. AC differences were seen in baseline-to-follow-up changes in weight (-3.62 vs. -0.52 kg), %body fat (-1.3 vs. 0%), moderate-to-vigorous physical activity (+224 vs. +115 min/week), caloric density (-0.3 vs. 0 kcal/g), serum leptin (-12.3 vs. -4.0 ng/dl) and upregulation of tumor PI3Kinase signaling and cell cycle-apoptosis related genes (CC-ARG; all p-values <0.05). Cytolytic CD56dim NK cell expression was positively associated with weight loss; CC-ARG increased with physical activity. Increased tumor (nuclear) TNFα and IL-1ß, CX3CL1 and CXCL1 gene expression was observed in the WLI. Tumor Ki67 did not differ between arms. Feasibility benchmarks included 80% accrual, 100% retention, no adverse effects and excellent adherence. Short-term weight loss interventions are feasible; however, mixed effects on tumor biology suggest unclear benefit to presurgical caloric restriction, but possible benefits of physical activity.

Spinal cord stimulation failure: evaluation of factors underlying hardware explantation.

OBJECTIVE: Spinal cord stimulation has been shown to improve pain relief and reduce narcotic analgesic use in cases of complex refractory pain syndromes. However, a subset of patients ultimately undergoes removal of the spinal cord stimulator (SCS) system, presumably because of surgical complications or poor efficacy. This retrospective study addresses the paucity of evidence regarding risk factors and underlying causes of spinal cord stimulation failures that necessitate this explantation. METHODS: In this retrospective single-center review, 129 patients underwent explantation of SCS hardware during a 9-year period (2005-2013) following initial placement at the authors' institution or elsewhere. Medical history, including indication of implantation, device characteristics, revision history, and reported reasons for removal of hardware, were reviewed. RESULTS: The 74 (57%) women and 55 (43%) men were a median of 49 years old (IQR 41-61 years) at explantation; the median time to explantation was 20 months (IQR 7.5-45.5 months). Thoracic or upper lumbar leads were placed in 89.9% of patients primarily for the diagnosis of postsurgical failed-back surgery syndrome (70.5%), chronic regional pain syndrome (14.7%), and neuropathic pain (8.5%). More than half of patients were legally disabled. Initial postoperative reduction in pain was reported in 81% of patients, and 37.8% returned to work. Among 15 patients with acute postsurgical complications (12 infections, 2 hemorrhages, 1 immediate paraplegia), the median time to removal was 2 months. Primary reasons for hardware removal were lack of stimulation efficacy (81%), electrode failure due to migration (14%), and allergic reactions to implanted hardware in 2 patients. The 72 patients who underwent formal psychiatric evaluation before implantation were affected by high rates of major depression (64%), anxiety (34%), posttraumatic stress disorder (PTSD) (12%), drug or alcohol abuse (12%), and physical or sexual abuse (22%). CONCLUSIONS: The authors' findings provide insight regarding the mechanisms of spinal cord stimulation failure that resulted in total removal of the implanted system. The relationship between spinal cord stimulation failure and certain psychiatric disorders, such as PTSD, depression, and anxiety, is highlighted. Ultimately, this work may shed light on potential avenues to reduce morbidity and improve patient outcomes.

Mutations in the S-Adenosylmethionine Synthetase Genes SAM1 and SAM2 Differentially Affect Genome Stability in Saccharomyces cerevisiae.

Maintenance of genome integrity is a crucial cellular focus that involves a wide variety of proteins functioning in multiple processes. Defects in many different pathways can result in genome instability, a hallmark of cancer. Utilizing a diploid Saccharomyces cerevisiae model, we previously reported a collection of gene mutations that affect genome stability in a haploinsufficient state. In this work we explore the effect of gene dosage on genome instability for one of these genes and its paralog; SAM1 and SAM2 These genes encode S-Adenosylmethionine (AdoMet) synthetases, responsible for the creation of AdoMet from methionine and ATP. AdoMet is the universal methyl donor for methylation reactions and is essential for cell viability. It is the second most used cellular enzyme substrate and is exceptionally well-conserved through evolution. Mammalian cells express three genes, MAT1A, MAT2A, and MAT2B, with distinct expression profiles and functions. Alterations to these AdoMet synthetase genes, and AdoMet levels, are found in many cancers, making them a popular target for therapeutic intervention. However, significant variance in these alterations are found in different tumor types, with the cellular consequences of the variation still unknown. By studying this pathway in the yeast system, we demonstrate that losses of SAM1 and SAM2 have different effects on genome stability through distinctive effects on gene expression and AdoMet levels, and ultimately separate effects on the methyl cycle. Thus, this study provides insight into the mechanisms by which differential expression of the SAM genes have cellular consequences that affect genome instability.

The Triality of Strain, Self-Control, and Eating Disorders.

This study examines the potential relationship between eating disorders and antisocial behaviors through the lenses of the general theory of crime and general strain theory. We utilized the data from the National Longitudinal Study of Adolescent to Adult Health, a longitudinal study of a nationally representative sample of juveniles in grades 7 to 12 in the United States between 1994 and 2008. We constructed three separate measures of eating disorders and examined their relationships with both petty theft and aggressive behaviors. Results indicated that previous traumatic experiences (such as sexual abuse) are consistent risk factors for eating disorders, and that eating disorders can increase antisocial involvements. Moreover, eating disorders can diminish self-control and agitate depressed moods, which may increase the likelihood of both petty theft and violent conduct, and this effect can extend to later adulthood as well.

Management of autonomic dysreflexia associated with Charcot spinal arthropathy in a patient with complete spinal cord injury: Case report and review of the literature.

BACKGROUND: Charcot spinal arthropathy (CSA) clearly represents a challenge in long-term spinal cord injury patients, one that can have extremely uncomfortable and potentially lethal outcomes if not managed properly. CASE DESCRIPTION: A 66-year-old man with a history of complete C7 quadriplegia presented with new-onset autonomic dysreflexia that resulted from Charcot spinal arthropathy (CSA). Pathologic instability, in the atypical site of the mid-thoracic spine, spanning from the T8-T9 vertebral levels was appreciated on physical exam as an audible, palpable, and visible dynamic kyphosis; kyphosis was later confirmed on neuroimaging. Based on the CSA severity and sequelae, the patient underwent bilateral decompression laminectomy with lateral extracavitary arthrodesis and posterior instrumentation. Symptoms dramatically improved and at 1-year follow-up, dynamic thoracic kyphosis and most symptoms of autonomic dysreflexia had resolved. CONCLUSIONS: Based on our case and published reports, vigilant imaging and thorough physical examination in long-standing spinal cord injury could help early diagnosis and treatment of CSA, theoretically preventing development of cord atrophy and subsequent long-term sequelae. Surgical correction rather than bracing may be recommended in patients who have complete injury at or above T6 in patients with symptoms of autonomic dysreflexia associated with CSA confirmed on neuroimaging.