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Study Design: Retrospective cohort., Objective: To evaluate the impact of adjunctive gabapentinoid therapy on postoperative opioid consumption following 1-3 levels anterior lumbar interbody fusion (ALIF) with posterior fixation., Summary of Background Data: Gabapentin and pregabalin are analogues of the inhibitory neurotransmitter Gamma-Aminobutyric Acid (GABA) and are frequently employed as adjuncts in multimodal anesthesia strategies for managing acute pain. However, the opioid-sparing effect of gabapentinoids in the context of spine surgery has yet to be consistently demonstrated., Methods: The PearlDiver Database was queried from 2010 to 2021 for patients who underwent primary 1-3 levels ALIF with posterior fixation. Patients with opioid or gabapentinoid use within 6 months prior to index surgery were excluded. Patients with both gabapentinoid and opioid treatment were propensity score-matched to patients with opioid-only treatment., Results: The propensity score-matching resulted in two equal groups of 2,617 patients with and without adjunctive gabapentinoid treatment for pain management. Adjunctive use of gabapentinoids was associated with a modest 2.9% reduction in average Morphine Milligram Equivalent (MME) per day (Standardized Mean Difference (SMD) -1.33, 95% Confidence Interval (CI) [-2.657, -0.002], P=0.050). However, this was accompanied by a 37.1% increase in the total duration of opioid prescriptions (SMD 94.97, 95% CI [56.976, 132.967], P<0.001) and a 41.7% increase in total MME consumption per patient (SMD 4817.23, 95% CI [1864.410, 7770.044], P=0.001). Additionally, gabapentinoid use was associated with an increased risk of readmission due to pain (Relative Risk (RR) 1.10, 95% CI [1.002, 1.212], P=0.050) and the development of drug abuse (RR 1.37, 95% CI [1.016, 1.833], P=0.046)., Conclusion: Despite the modest daily opioid-sparing effect observed, adjunctive gabapentinoid treatment appears to increase total opioid consumption due to prolonged opioid use and may compromise pain management in the context of ALIF with posterior fixation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Study Design: Retrospective cohort., Objective: To evaluate the impact of semaglutide treatment for Type 2 Diabetes Mellitus (T2DM) on the risk of short-term (<6 months) postoperative complications in patients undergoing primary cervical spine decompression and fusion (CSDF)., Summary of Background Data: Semaglutide, a GLP-1 receptor agonist, is gaining popularity as a weekly injectable medication for the treatment of T2DM and obesity. Existing research indicates that higher levels of HbA1c and obesity are linked to fewer positive results after undergoing spine surgery, particularly cervical decompression and fusion. Nevertheless, there is a scarcity of publications evaluating the influence of semaglutide therapy on surgical complications, including surgical site infection, wound complications, and reoperation within 6 months, which were aggregated into a composite measure., Methods: The PearlDiver Database was queried from January 2010 to December 2021 for patients with a primary diagnosis of T2DM who underwent CSDF for degenerative pathology. Patients with semaglutide treatment within 6 months before index surgery were propensity score-matched to patients without the treatment, employing age, gender, and Charlson comorbidity index (CCI) as matching covariates. A multivariate regression model was used to investigate the impact of semaglutide treatment on postoperative surgical complications., Results: The propensity score-matched cohort included 596 patients (semaglutide cohort: 298, control cohort: 298). There were no statistically significant differences between cohorts in the composite measure of postoperative surgical complications following index CSDF (OR 1.26, 95% CI 0.83-1.93, P=0.331). Similarly, both 30-day (OR 0.83, 95% CI 0.49-1.42, P=0.589) and 90-day readmission rate (OR 0.89, 95% CI 0.56-1.42, P=0.724) were similar between both cohorts., Conclusion: This study suggests that in patients with T2DM, semaglutide treatment is not associated with higher rates of short-term adverse events after CSDF. The effect of semaglutide use on long-term outcomes remains unknown., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Study Design: Retrospective cohort., Objective: To compare rates of all-cause surgical and medical complications between zero-profile (ZP; stand-alone) implants versus any graft type with an 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. Although ACDFs performed with graft and plate have been the gold standard, more recently, ZP 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 ZP (stand-alone) implants to grafts with plating systems., Materials and Methods: Data were extracted from the PearlDiver Mariner Database using Current Procedural Terminology codes to classify patients into 1 level, 2 levels, and a total of 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 2 equal groups of 7284 patients who underwent 1-2 level ACDF with either grafting with a plate or ZP (stand-alone) implant. There were no statistically significant differences in all-cause surgical complications, pseudarthrosis rate, dysphagia, or need for revision surgery between both cohorts (risk ratio: 0.99, 95% CI: 0.80-1.21, P = 0.95). In addition, all-cause medical complications were similar between both cohorts (risk ratio: 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 ZP (stand-alone) implants have similar outcomes compared with grafts with plating systems, with no observed differences in all-cause surgical or medical complications profile., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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=Nwd 2 ). 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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Study Design: Systematic review and meta-analysis., Objective: To perform a systematic review and meta-analysis investigating the rate of adverse events after spine surgery in patients who underwent bariatric surgery (BS)., Summary of Background Data: Obesity is an established risk factor for postoperative complications after spine surgery. BS has been associated with improvements in health in patients with severe obesity. However, it is not known whether undergoing BS before spine surgery is associated with reduced adverse outcomes., Materials and Methods: PubMed, EMBASE, Scopus, and Web-of-Science were systematically searched according to "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" guidelines. The search included indexed terms and text words from database inception to the date of the search (May 27, 2022). Data and estimates were pooled using the Mantel-Haenszel method for random-effects meta-analysis. Risk of bias was assessed using the Joanna Briggs Institute risk of bias tool. The primary outcome was an all-cause complication rate after surgery. Relative risks for surgical and medical complications were assessed., Results: A total of 4 studies comprising 177,273 patients were included. The pooled analysis demonstrated that the all-cause medical complication rate after spine surgery was lower in patients undergoing BS (relative risk: 0.54, 95% CI: 0.39, 0.74, P < 0.01). There was no difference in rates of surgical complications and 30-day hospital readmission rates between the cohort undergoing BS before spine surgery and the cohort that did not., Conclusion: These analyses suggest that obese patients undergoing BS before spine surgery have significantly lower adverse event rates. Future prospective studies are needed to corroborate these findings., Level of Evidence: 4., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The safety, efficacy, and pharmacokinetics of copanlisib were evaluated in this phase Ib/II study in Japanese patients with relapsed/refractory indolent non-Hodgkin lymphoma (NHL). The primary endpoint was safety at the recommended dose; efficacy endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival. In phase Ib, patients received copanlisib 45 mg intravenously on days 1, 8, and 15 of a 28-day cycle, and when tolerated, consecutive patients received copanlisib 60 mg. As no dose-limiting toxicities occurred at the 45 mg (n = 3) or 60 mg (n = 7) dose in phase Ib, the recommended dose for Japanese patients was determined to be 60 mg, and this dose was used in phase II (n = 15). Although all patients experienced at least one treatment-emergent adverse event (TEAE), with hyperglycemia being the most common AE, no AE-related deaths were reported. The ORR was 68.0% (17/25 patients), median PFS was 302 (95% CI 231-484) days, and the duration of response was 330 (range 65-659) days. The pharmacokinetic properties of copanlisib were similar between Japanese and non-Japanese patients. Overall, copanlisib 60 mg had an acceptable safety profile and showed promising antitumor activity in Japanese patients with relapsed/refractory indolent NHL., (© 2022. The Author(s).)

Purpose: Copanlisib, a pan-PI3K inhibitor, has previously shown clinical efficacy and a tolerable safety profile in patients with indolent non-Hodgkin lymphoma. However, the pharmacokinetics, safety, tolerability, and efficacy of copanlisib in Chinese patients have not been reported., Methods: This was a single-arm, open-label, phase I study of copanlisib in Chinese patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL). Patients received a single intravenous 60 mg infusion of copanlisib over 1 h on days 1, 8, and 15 of a 28-day cycle, with 1 week of rest. Safety was monitored throughout the study, and plasma copanlisib levels were measured for pharmacokinetic analysis. Tumor response was determined by independent central radiologic review., Results: Sixteen patients were enrolled and 13 were treated with 60 mg of copanlisib for a median of 15.0 weeks. With a C max of 566 μg/L and a AUC (0-24) of 1880 μg·h/L following single intravenous infusion, the pharmacokinetic parameters of copanlisib were consistent with that in previous studies, and no accumulation in plasma was observed. Treatment-emergent adverse events were reported for all 13 patients, the most common of which were hyperglycemia (100.0%), hypertension (76.9%), decreased neutrophil count (76.9%), and decreased white blood cell count (69.2%). Seven out of 12 evaluated patients achieved partial response, resulting in an overall response rate of 58.3% CONCLUSIONS: Copanlisib was well tolerated in Chinese patients with relapsed or refractory iNHL at the dose of 60 mg and demonstrated encouraging disease control, thus warranting further clinical investigation., Clinical Trial Registration Number: NCT03498430 (April 13, 2018)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hands-on ultrasound experience has become a desirable component for undergraduate medical education (UGME) curricula throughout medical schools in the United States (US) to enhance readiness for future training. Ultrasound integration can be a useful assistive educational method in undergraduate medical education to improve anatomy and physiology skills. Relatively few medical schools have integrated ultrasound experiences formally into their 4-year medical school curriculum due to limitations of a resource intensive set up., Methods: We undertook a scoping review of published UGME ultrasound curricula integrated into all four years in peer-reviewed as well online literature. In addition, we provide a narrative review of our institutional experience in conceptualization, design and implementation of UGME ultrasound curriculum driven by need to address the fading knowledge in anatomy and physiology concepts beyond pre-clinical years., Results: Integrated ultrasound curriculum at WFSOM utilizes focused ultrasonography as a teaching aid for students to gain a more thorough understanding of basic and clinical science concepts taught in the medical school curriculum. We found 18 medical schools with ultrasound curricula published in peer-reviewed literature with a total of 33 ultrasound programs discovered by adding Google search and personal communication CONCLUSIONS: The results of the review and our institutional experience can help inform future educators interested in developing similar curricula in their undergraduate programs. Common standards, milestones and standardized competency-based assessments would be helpful in more widespread application of ultrasound in UGME curricula.

Marginal zone lymphoma (MZL) is challenging to treat, with many patients relapsing following initial treatment. We report the long-term efficacy and safety of copanlisib, a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in the subset of 23 patients with relapsed/refractory MZL treated in the phase 2 CHRONOS-1 study (#NCT01660451, Part B; www.clinicaltrials.gov). Patients had a median of 3 prior lines of therapy, including rituximab and alkylating agents, and received IV copanlisib 60 mg on days 1, 8, and 15 of 28-day cycles for a median of 23 weeks. The objective response rate was 78.3% (18/23; 3 complete responses and 15 partial responses). The median duration of response was 17.4 months (median follow-up, 9.4 months), and median time to response was 2.1 months. Median progression-free survival was 24.1 months (median follow-up, 10.3 months), and median overall survival was not reached (median follow-up, 28.4 months). The most common all-grade treatment-emergent adverse events (TEAEs) included fatigue (52.2%, 12/23), diarrhea, and transient, infusion-related hyperglycemia (each 47.8%, 11/23). Nineteen patients (82.6%) had grade 3/4 TEAEs, most commonly transient, infusion-related hyperglycemia and hypertension (each 39.1%, 9/23). TEAEs led to dose reduction or dose interruptions /delays in 9 patients (39.1%) and 18 patients (78.3%), respectively. Patients with activated PI3K/B-cell antigen receptor signaling had improved response rates. Overall, copanlisib demonstrated strong efficacy, with a short time to objective response, improved objective response rate with longer treatment duration, durable responses, and manageable safety, in line with previous reports. These data provide rationale for long-term treatment with copanlisib in patients with relapsed/refractory MZL., (© 2021 by The American Society of Hematology.)

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors., (© 2019 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)

Purpose Phosphatidylinositol 3-kinase (PI3K) signaling is critical for the proliferation and survival of malignant B cells. Copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3K-α and -δ isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma. Patients and Methods In this phase II study, 142 patients with relapsed or refractory indolent lymphoma after two or more lines of therapy were enrolled to receive copanlisib 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle. The primary end point was objective response rate; secondary end points included duration of response, progression-free survival, and overall survival. In addition, safety and gene expression were evaluated. Results Median age was 63 years (range, 25 to 82 years), and patients had received a median of three (range, two to nine) prior regimens. The objective response rate was 59% (84 of 142 patients); 12% of patients achieved a complete response. Median time to response was 53 days. Median duration of response was 22.6 months, median progression-free survival was 11.2 months, and median overall survival had not yet been reached. The most frequent treatment-emergent adverse events were transient hyperglycemia (all grades, 50%; grade 3 or 4, 41%) and transient hypertension (all grades, 30%; grade 3, 24%). Other grade ≥3 events included decreased neutrophil count (24%) and lung infection (15%). High response rates to copanlisib were associated with high expression of PI3K/B-cell receptor signaling pathway genes. Conclusion PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma.

The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m(2)/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.

Vorinostat is a potent histone deacetylase inhibitor that blocks the catalytic site of these enzymes. A large number of cellular proteins are modified post-translationally by acetylation, leading to altered structure and/or function. Many of these proteins, such as core nucleosomal histones and transcription factors, function in key cellular processes and signal transduction pathways that regulate cell growth, migration, and differentiation. At concentrations that are non-toxic to normal cells, vorinostat dramatically alters cellular acetylation patterns and causes growth arrest and death and in a wide range of transformed cells, both in vitro and in animal tumor models. Vorinostat has shown promising clinical activity against hematologic and solid tumors at doses that have been well tolerated by patients. Recent non-clinical experiments that explored the effects of vorinostat in combination with other chemotherapeutic agents have begun to illuminate potential mechanisms of action for this histone deacetylase inhibitor and are providing guidance for new avenues of clinical investigation.

Vorinostat (Zolinza), a histone deacetylase inhibitor, was approved by the US Food and Drug Administration in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. This review summarizes evidence on the use of vorinostat in solid and hematologic malignancies and collated tolerability data from the vorinostat clinical trial program. Pooled vorinostat clinical trial data from 498 patients with solid or hematologic malignancies show that vorinostat was well tolerated as monotherapy or combination therapy. The most commonly reported drug-related adverse events (AEs) associated with monotherapy (n = 341) were fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%), and Grade 3/4 drug-related AEs included fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.3%), and decreased platelet count (5.3%). The most common drug-related AEs observed with vorinostat in combination therapy (n = 157, most of whom received vorinostat 400 mg qd for 14 days) were nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), vomiting (31.2%), and anorexia (20.4%), with the majority of AEs being Grade 2 or less. In Phase I trials, combinations with vorinostat were generally well tolerated and preliminary evidence of anticancer activity as monotherapy or in combination with other systemic therapies has been observed across a range of malignancies. Ongoing and planned studies will further evaluate the potential of vorinostat in combination therapy, including combinations with radiation, in patients with diverse malignancy types, including non-small-cell lung cancer, glioblastoma multiforme, multiple myeloma, and myelodysplastic syndrome.