Background Although the Revitalization Act was passed in 1993 to increase enrollment of women in clinical trials, there has been little focus on sex disparity in basic and translational research. We ...hypothesize that sex bias exists in surgical biomedical research. Methods Manuscripts from Annals of Surgery , American Journal of Surgery , JAMA Surgery , Journal of Surgical Research , and Surgery from 2011 to 2012 were reviewed. Data abstracted included study type, sex of the animal or cell studied, location, and presence of sex-based reporting of data. Results Of 2,347 articles reviewed, 618 included animals and/or cells. For animal research, 22% of the publications did not specify the sex of the animals. Of the reports that did specify the sex, 80% of publications included only males, 17% only females, and 3% both sexes. A greater disparity existed in the number of animals studied: 16,152 (84%) male and 3,173 (16%) female ( P < .0001). For cell research, 76% of the publications did not specify the sex. Of the papers that did specify the sex, 71% of publications included only males, 21% only females, and 7% both sexes. Only 7 (1%) studies reported sex-based results. For publications on female-prevalent diseases, 44% did not report the sex studied. Of those reports that specified the sex, only 12% studied female animals. More international than national (ie, United States) publications studied only males (85% vs 71%, P = .004), whereas more national publications did not specify the sex (47% vs 20%, P < .0001). A subanalysis of a single journal showed that across three decades, the number of male-only studies and usage of male animals has become more disparate over time. Conclusion Sex bias, be it overt, inadvertent, situational, financial, or ignorant, exists in surgical biomedical research. Because biomedical research serves as the foundation for subsequent clinical research and medical decision-making, it is imperative that this disparity be addressed because conclusions derived from such studies may be specific to only one sex.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective
To investigate the results of real-world application of non-myeloablative autologous HSCT for multiple sclerosis (MS).
Methods
Between July 2003 and October 2019 at a single center ...(Northwestern University), 414 patients with relapsing remitting MS (RRMS) and 93 patients with newly diagnosed secondary progressive MS (SPMS) underwent non-myeloablative HSCT.
Results
There was one treatment-related death (0.19%) due to hospital-acquired legionella pneumonia, and one patient developed neutropenic bacteremia (
Klebsiella pneumonia)
without sepsis
.
Overall 5-year survival was 98.8%. Post HSCT secondary autoimmune diseases (2nd ADs) were idiopathic thrombocytopenia (ITP) and hypo or hyperthyroidism. ITP was highest with alemtuzumab (14%) and 0 to 2.8% for the non-alemtuzumab regimens. After HSCT, 16 patients developed hypothyroidism (3.5%) and 15 developed hyperthyroidism / Grave’s disease (3.3%). Relapse free survival (RFS) at 5 years for RRMS and SPMS was 80.1% and 98.1%, respectively, while progression free survival (PFS) at 4 years for RRMS and SPMS was 95% versus 66%, respectively. For patients with RRMS, the EDSS significantly improved (
p
< 0.0001) at each follow-up from a pre-HSCT mean of 3.87 to 2.51, 2.50, 2.41, 2.33, and 2.19 at 1, 2, 3, 4, and 5 years, respectively. For SPMS, the EDSS improved significantly only at 1 year but not thereafter. For SPMS, the mean baseline EDSS of 5.09 changed post-HSCT to 4.85 (
p
= 0.04), 4.88 (
p
= 0.2), 4.92 (
p
= .27), 4.72 (
p
= 0.07), and 4.2 (
p
= 0.21) at 1, 2, 3, 4, 5 years, respectively.
Conclusion
In patients with RRMS, autologous non-myeloablative HSCT is an effective one-time therapy, while HSCT appears of less benefit for newly diagnosed SPMS.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
IMPORTANCE: Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS). ...OBJECTIVE: To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression. DESIGN, SETTING, AND PARTICIPANTS: Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 10 = worst neurologic disability) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018. INTERVENTIONS: Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55). MAIN OUTCOMES AND MEASURES: The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. RESULTS: Among 110 randomized patients (73 66% women; mean age, 36 SD, 8.6 years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, −1.7; 95% CI, −2.03 to −1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events). CONCLUSIONS AND RELEVANCE: In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00273364
Survivors of cancer in the United States are often financially encumbered by expenses and lost wages from cancer treatment. The majority of patients with thyroid cancer are diagnosed before age 65, ...when they are not eligible for Medicare. We hypothesized that financial distress would be common among thyroid cancer survivors and would be associated with poor health-related quality of life.
A financial distress questionnaire and Patient-Reported Outcomes Measurement Information System (29-item) were completed online by 1,743 adult thyroid cancer survivors living in the United States. Multivariable modeling was used to identify variables which independently predicted poor health-related quality of life. The magnitude of predicted change was estimated by β coefficients and 95% confidence intervals. A β ≥3 was considered clinically significant; α was set at 0.01.
Financial difficulties were reported by 43% of thyroid cancer survivors and were associated with worse anxiety (β = 5.07; P < .01) and depression (β = 5.47; P < .01). Living in poverty was associated with worse anxiety (β = 4.14; P < .01) and depression (β = 4.35; P < .01). Lost productivity at work was associated with worse fatigue (β = 5.99; P < .01) and social functioning (β = –4.07; P < .01). Inability to change jobs was associated with worse fatigue (β = 3.08; P < .01), pain interference (β = 3.56; P < .01), and social functioning (β = –3.09; P < .01). Receiving disability benefits was associated with worse pain interference (β = 3.93; P < .01). Impaired ability to obtain a job was associated with worse social functioning (β = –3.02; P < .01). Reported unemployment rate was 12.3%.
Financial distress and negative financial events were common among thyroid cancer survivors and were associated with poorer health-related quality of life across 5 Patient-Reported Outcomes Measurement Information System health domains.
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Depression is a distressing side effect of cancer and its treatment. In the general population, exercise is an effective antidepressant.
We conducted a systematic review and meta-analysis to ...determine the antidepressant effect of exercise in cancer survivors.
In May 2011, we searched MEDLINE, PsycInfo, EMBASE, CINAHL, CDSR, CENTRAL, AMED, Biosis Previews, and Sport Discus and citations from relevant articles and reviews.
We included randomized controlled trials (RCT) comparing exercise interventions with usual care in cancer survivors, using a self-report inventory or clinician rating to assess depressive symptoms, and reporting symptoms pre- and postintervention.
Around 7,042 study titles were identified and screened, with 15 RCTs included.
Effect sizes (ES) were reported as mean change scores. The Q test was conducted to evaluate heterogeneity of ES. Potential moderator variables were evaluated with examination of scatter plots and Wilcoxon rank-sum or Kruskal-Wallis tests.
The overall ES, under a random-effects model, was -0.22 (confidence interval, -0.43 to -0.09; P = 0.04). Significant moderating variables (ps < 0.05) were exercise location, exercise supervision, and exercise duration.
Only one study identified depression as the primary endpoint.
Exercise has modest positive effects on depressive symptoms with larger effects for programs that were supervised or partially supervised, not conducted at home, and at least 30 minutes in duration.
Our results complement other studies showing that exercise is associated with reduced pain and fatigue and with improvements in quality of life among cancer survivors.
Multiple studies have shown that gut microbes contribute to atherosclerosis, and there is mounting evidence that microbial metabolism of dietary nutrients influences pathophysiology. We hypothesized ...that indole- and phenyl-derived metabolites that originate solely or in part from bacterial sources would differ between patients with advanced atherosclerosis and age- and sex-matched controls without clinically apparent atherosclerosis.
Plasma from the advanced atherosclerosis cohort (n = 100) was from patients who underwent carotid endarterectomy, open infrainguinal leg revascularization, or major leg amputation for critical limb ischemia. The controls (n = 22) were age- and sex-matched participants who had no peripheral arterial disease or history of stroke or myocardial infarction. Patients with chronic kidney disease were excluded. Metabolites and internal standards were measured using high-performance liquid chromatography and tandem mass spectrometry.
Plasma metabolite concentrations differed significantly between the advanced atherosclerosis and control cohorts. After adjustment for traditional atherosclerosis risk factors, indole (odds ratio OR, 0.84; 95% confidence interval CI, 0.75-0.95; P = .004), tryptophan (OR, <0.001; 95% CI, <0.001-0.003; P < .001), indole-3-propionic acid (OR, 0.27; 95% CI, 0.019-0.91; P = .02), and indole-3-aldehyde (OR, 0.12; 95% CI, 0.014-0.92; P = .04) concentrations negatively associated with advanced atherosclerosis, whereas the kynurenine/tryptophan ratio (OR, 61.7; 95% CI, 1.9->999; P = .02) was positively associated. Furthermore, tryptophan and indole-3-propionic acid concentrations (Spearman coefficients of 0.63 and 0.56, respectively; P < .001) correlated with the ankle-brachial index, a surrogate for overall atherosclerotic disease burden. Fourteen patients experienced a major postoperative cardiac complication within 30 days in the advanced atherosclerosis cohort, which was associated with baseline kynurenine/tryptophan ratio (P = .001) and hippuric acid (P = .03). In a multivariate analysis, only the kynurenine/tryptophan ratio remained significantly associated with a postoperative cardiac complication (OR, 44.1; 95% CI, 3.3-587.1; P = .004). Twenty patients in the advanced atherosclerosis cohort experienced a major adverse cardiac event during the follow-up period, which was associated with hippuric acid (P = .002) and the kynurenine/tryptophan ratio (P < .001) at baseline. Both hippuric acid and the kynurenine/tryptophan ratio were independently associated with a major adverse cardiac event in multivariate analyses that included diabetes mellitus.
Specific microbe-derived metabolite signatures associate with advanced human atherosclerosis and postoperative cardiac complications. We suggest that these metabolites are potential novel biomarkers for atherosclerotic disease burden and that further investigation into mechanistic links between defined microbial metabolic pathways and cardiovascular disease is warranted.
Multiple studies have shown that the gut microbiome contributes to atherosclerosis, potentially through bioactive metabolites derived from commensal organisms. We performed a targeted metabolomic study of specific indole- and phenyl-derived metabolites that originate solely or in part from gut microbes. We found that the plasma concentrations of many of these metabolites differed in patients with advanced atherosclerosis and age- and gender-matched controls and that the concentrations of some of these metabolites correlated with postoperative outcomes in the advanced atherosclerosis cohort. These metabolites and their biotransformants are worthy of further investigation as potentially important biomarkers or modulators of atherosclerosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To improve the curability of older patients with newly diagnosed Hodgkin lymphoma.
We conducted a multicenter phase II study that administered brentuximab vedotin (Bv) sequentially before and after ...standard doxorubicin, vinblastine, and dacarbazine (AVD) for untreated patients with Hodgkin lymphoma age 60 years or older. After two lead-in doses of single-agent Bv (1.8 mg/kg once every 3 weeks), patients received six cycles of AVD chemotherapy followed by four consolidative doses of Bv in responding patients.
Patient characteristics included median age of 69 years (range, 60 to 88 years), 63% male, median Eastern Cooperative Oncology Group performance status 1, 81% stage III to IV disease, 60% International Prognostic Score 3 to 7, median Cumulative Illness Rating Scale-Geriatric comorbidity score of 7 (52% grade 3 to 4); and 12% had loss of instrumental activities of daily living at diagnosis. Thirty-seven (77%) of 48 patients completed six cycles of AVD, and 35 patients (73%) received at least one Bv consolidation. Overall response and complete remission rates after initial Bv lead-in dose were 18 (82%) of 22 and 8 (36%) of 22, respectively, and 40 (95%) of 42 and 34 (90%) of 42, respectively, after six cycles of AVD among 42 response-evaluable patients. Twenty (42%) of 48 patients experienced a grade 3 to 4 adverse event, most commonly neutropenia (44%), febrile neutropenia and pneumonia (8%), or diarrhea (6%); 33% had grade 2 peripheral neuropathy, which was reversible in a majority of patients. By intent-to-treat, the 2-year event-free survival, progression-free survival, and overall survival rates were 80%, 84%, and 93%, respectively. Furthermore, 2-year progression-free survival rates for patients with a Cumulative Illness Rating Scale-Geriatric comorbidity score of ≥ 10 versus < 10 were 45% versus 100%, respectively (
< .001), and with baseline loss versus no loss of instrumental activities of daily living were 25% versus 94% (
< .001), respectively, the latter persisting on multivariable analyses.
Altogether, sequential Bv-AVD was well tolerated and was associated with robust outcomes. Furthermore, geriatric-based measures were strongly associated with patient survival.
Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood–brain barrier. We aimed to assess the safety and pharmacokinetics ...of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma.
We conducted a dose-escalation phase 1 clinical trial in adults (aged ≥18 years) with recurrent glioblastoma, a tumour diameter of 70 mm or smaller, and a Karnofsky performance status of at least 70. A nine-emitter ultrasound device was implanted into a skull window after tumour resection. LIPU-MB with intravenous albumin-bound paclitaxel infusion was done every 3 weeks for up to six cycles. Six dose levels of albumin-bound paclitaxel (40 mg/m2, 80 mg/m2, 135 mg/m2, 175 mg/m2, 215 mg/m2, and 260 mg/m2) were evaluated. The primary endpoint was dose-limiting toxicity occurring during the first cycle of sonication and albumin-bound paclitaxel chemotherapy. Safety was assessed in all treated patients. Analyses were done in the per-protocol population. Blood–brain barrier opening was investigated by MRI before and after sonication. We also did pharmacokinetic analyses of LIPU-MB in a subgroup of patients from the current study and a subgroup of patients who received carboplatin as part of a similar trial (NCT03744026). This study is registered with ClinicalTrials.gov, NCT04528680, and a phase 2 trial is currently open for accrual.
17 patients (nine men and eight women) were enrolled between Oct 29, 2020, and Feb 21, 2022. As of data cutoff on Sept 6, 2022, median follow-up was 11·89 months (IQR 11·12–12·78). One patient was treated per dose level of albumin-bound paclitaxel for levels 1 to 5 (40–215 mg/m2), and 12 patients were treated at dose level 6 (260 mg/m2). A total of 68 cycles of LIPU-MB-based blood–brain barrier opening were done (median 3 cycles per patient range 2–6). At a dose of 260 mg/m2, encephalopathy (grade 3) occurred in one (8%) of 12 patients during the first cycle (considered a dose-limiting toxicity), and in one other patient during the second cycle (grade 2). In both cases, the toxicity resolved and treatment continued at a lower dose of albumin-bound paclitaxel, with a dose of 175 mg/m2 in the case of the grade 3 encephalopathy, and to 215 mg/m2 in the case of the grade 2 encephalopathy. Grade 2 peripheral neuropathy was observed in one patient during the third cycle of 260 mg/m2 albumin-bound paclitaxel. No progressive neurological deficits attributed to LIPU-MB were observed. LIPU-MB-based blood–brain barrier opening was most commonly associated with immediate yet transient grade 1–2 headache (12 71% of 17 patients). The most common grade 3–4 treatment-emergent adverse events were neutropenia (eight 47%), leukopenia (five 29%), and hypertension (five 29%). No treatment-related deaths occurred during the study. Imaging analysis showed blood–brain barrier opening in the brain regions targeted by LIPU-MB, which diminished over the first 1 h after sonication. Pharmacokinetic analyses showed that LIPU-MB led to increases in the mean brain parenchymal concentrations of albumin-bound paclitaxel (from 0·037 μM 95% CI 0·022–0·063 in non-sonicated brain to 0·139 μM 0·083–0·232 in sonicated brain 3·7-times increase, p<0·0001) and carboplatin (from 0·991 μM 0·562–1·747 in non-sonicated brain to 5·878 μM 3·462–9·980 μM in sonicated brain 5·9-times increase, p=0·0001).
LIPU-MB using a skull-implantable ultrasound device transiently opens the blood–brain barrier allowing for safe, repeated penetration of cytotoxic drugs into the brain. This study has prompted a subsequent phase 2 study combining LIPU-MB with albumin-bound paclitaxel plus carboplatin (NCT04528680), which is ongoing.
National Institutes of Health and National Cancer Institute, Moceri Family Foundation, and the Panattoni family.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is a paucity of patient-reported data on thyroidectomy scar perception. The effect of neck scarring on quality of life is not known. We hypothesized that worse perception of neck appearance ...would be related to worse health-related quality of life and that perception improves with time.
Survivors of thyroid cancer (n = 1,710) were surveyed online. Respondents were asked to score the appearance of their neck via a 5-point Likert scale. Quality of life was evaluated via the Patient-Reported Outcomes Measurement Information System 29. The relationships between neck appearance, patient characteristics, quality of life, and Patient-Reported Outcomes Measurement Information System domains were analyzed with multivariable models and Spearman partial correlations (rs).
Older age was associated with better perception of neck appearance (odds ratio 0.975/year; 95% confidence interval 0.967–0.983; P < .001). Greater time since surgery was also associated with improved perception (odds ratio 0.962/year; 95% confidence interval 0.947–0.977; P < .0001). We observed no statistically significant difference between current and preoperative baseline perception >2 years after surgery. On multivariable analysis, age >45 years, >2 years since surgery, and higher self-reported quality of life were independent predictors of better self-reported neck appearance (P ≤ .0003). In patients ≤2 years after surgery (n = 568), the PROMIS domains of anxiety, depression, social function, and fatigue had weak but statistically significant correlations with worse perception of neck appearance (P < .0001).
Age >45, >2 years since surgery, and higher quality of life were independently associated with better self-reported neck appearance. Perception of neck appearance returned to preoperative baseline 2 years after surgery. PROMIS domains had a weak but significant association with neck appearance perception in patients ≤2 years after surgery. The impact of post-thyroidectomy neck appearance on quality of life appears to be mild and transient and returns to preoperative levels after 2 years.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Thyroid cancer survivors are a rapidly growing population in the United States. The factors that drive health-related quality of life (HRQOL) in this population have not been well characterized. We ...hypothesized that more aggressive treatments and greater treatment-related adverse effects would be associated with worse HRQOL scores in thyroid cancer survivors.
Thyroid cancer survivors (18–89 years of age) completed an online survey regarding their clinical history in addition to the Patient-Reported Outcomes Measurement Information System (PROMIS) 29 instrument. Univariable and multivariable modeling were performed to evaluate factors associated with worse HRQOL scores. We generated β-values and 95% confidence intervals to quantify the effect of each independent variable in the model.
Thyroid cancer survivors (n = 1,743) reported a high incidence of complications related to surgery and radioactive iodine ablation. Postoperative dysphonia (ß 1.83–3.07) and dysphagia (ß 2.05–3.65) predicted worse HRQOL scores across multiple PROMIS domains. Younger patient age (age <45 years) and short- or long-term complications of radioactive iodine, including gastrointestinal symptoms (51.9%), appetite changes (71.2%), sialadenitis (58.1%), xerostomia (73.3%), and xerophthalmia (45.1%) were associated with worse HRQOL scores (P < .01).
The factors associated with significantly worse HRQOL scores across multiple PROMIS domains for thyroid cancer survivors included patient age <45 years, postoperative hypocalcemia, dysphonia, dysphagia, scar appearance, and complications from radioactive iodine. Methods of evaluation, management, and prevention of these factors might positively impact HRQOL.
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