Editorial Commentary: Postoperative Zoledronic Acid Improves Tendon Healing but Does Not Affect Outcomes in Rotator Cuff Repair Patients With Postmenopausal Osteoporosis.

Understanding the preoperative risk factors for successful rotator cuff repair (RCR) and ways to optimize these factors is an evolving area of study. The Rotator Cuff Healing Index and other proxy risk factors for failed rotator cuff healing have implicated significant fatty infiltration, muscular atrophy, advanced chronological age, tear size and retraction, and ultimately, osteoporosis. Although structural (or biological) augmentation and tendon transfer have been proposed as solutions for the alarmingly high rate of failure after primary RCR, other options may preferentially focus on the enthesis and underlying osseous footprint. Currently, bisphosphonates are frequently used in the treatment of osteoporosis and prevention of fragility fractures. However, burgeoning evidence suggests that postoperative zoledronic acid may have clinical utility after rotator cuff and other tendon repairs. In the cost-conscious world of evidence-based medicine, the added economic burden of additional medications and office visits may or may not improve patient outcomes-much less confer added value. Our advice to fellow shoulder surgeons: Wait for further information, but continue to holistically consider and optimize risk factors for poor soft-tissue healing. Although the addition of postoperative bisphosphonates may improve suture anchor fixation and promote a better foundation for healing, it will not immediately transform your RCR success rates.

Bioactive and Bioinductive Implants Are Increasingly Used in Orthopaedic Sports Medicine but Adequately Controlled Studies Are Needed: A Scoping Review.

PURPOSE: To describe the currently available literature reporting clinical outcomes for bioactive and bioinductive implants in sports medicine. METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search of 4 databases was completed to identify eligible studies. Inclusion criteria were studies using bioactive or bioinductive implants in human clinical studies for sports medicine procedures. Data were extracted and reported in narrative form, along with study characteristics. RESULTS: In total, 145 studies were included involving 6,043 patients. The majority of included studies were level IV evidence (65.5%), and only 36 included a control group (24.8%). Bioactive materials are defined as any materials that stimulate an advantageous response from the body upon implantation, whereas bioinductive materials provide a favorable environment for a biological response initiated by the host. Bioactivity can speed healing and improve clinical outcome by improving vascularization, osteointegration, osteoinduction, tendon healing, and soft-tissue regeneration or inducing immunosuppression or preventing infection. The most common implants reported were for knee (67.6%, primarily cartilage [most commonly osteochondral defects], anterior cruciate ligament, and meniscus), shoulder (16.6%, primarily rotator cuff), or ankle (11.7%, primarily Achilles repair). The most common type of implant was synthetic (44.1%), followed by autograft (30.3%), xenograft (16.6%), and allograft (9.0%). In total, 69% of implants were standalone treatments and 31% were augmentation. CONCLUSIONS: The existing bioactive and bioinductive implant literature in sports medicine is largely composed of small, low-level-of-evidence studies lacking a control group. CLINICAL RELEVANCE: Before bioactive implants can be adapted as a new standard of care, larger, comparative clinical outcome studies with long-term follow-up are essential.

Predictive factors influencing internal rotation following reverse total shoulder arthroplasty.

BACKGROUND: Reverse total shoulder arthroplasty (RTSA) is increasingly used as a treatment modality for various pathologies. The purpose of this review is to identify preoperative risk factors associated with loss of internal rotation (IR) after RTSA. METHODS: A systematic review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Ovid MEDLINE, Ovid Embase, and Scopus were queried. The inclusion criteria were as follows: articles in English language, minimum 1-year follow-up postoperatively, study published after 2012, a minimum of 10 patients in a series, RTSA surgery for any indication, and explicitly reported IR. The exclusion criteria were as follows: articles whose full text was unavailable or that were unable to be translated to English language, a follow-up of less than 1 year, case reports or series of less than 10 cases, review articles, studies in which tendon transfers were performed at the time of surgery, procedures that were not RTSA, and studies in which the range of motion in IR was not reported. RESULTS: The search yielded 3792 titles, and 1497 duplicate records were removed before screening. Ultimately, 16 studies met the inclusion criteria with a total of 5124 patients who underwent RTSA. Three studies found that poor preoperative functional IR served as a significant risk factor for poor postoperative IR. Eight studies addressed the impact of subscapularis, with 4 reporting no difference in IR based on subscapularis repair and 4 reporting significant improvements with subscapularis repair. Among studies with sufficient power, BMI was found to be inversely correlated with degree of IR after RTSA. Preoperative opioid use was found to negatively affect IR. Other studies showed that glenoid retroversion, component lateralization, and individualized component positioning affected postoperative IR. CONCLUSIONS: This study found that preoperative IR, individualized implant version, preoperative opioid use, increased body mass index and increased glenoid lateralization were all found to have a significant impact on IR after RTSA. Studies that analyzed the impact of subscapularis repair reported conflicting results.

A population level analysis of second hematological malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma survivors in the era of targeted therapies.

With improvement in survival after chronic lymphocytic leukemia (CLL) diagnosis, the real-world burden of second hematological malignancies (SHM) has not been comprehensively assessed in recent era. We analyzed risk, incidence, and outcomes of SHM in CLL patients between 2000 and 2019 using SEER database. CLL patients had greater risk for hematological malignancies than general population [SIR, standardized incidence ratio (95% CI):2.58 (2.46-2.70); p < 0.05]. The risk for subsequent lymphoma increased by 1.75 folds in 2015-2019 compared to 2000-2004. The duration, after CLL diagnosis, of maximum risk for SHM decreased as 60-119 months for time-period 2000-2004, 6-11 months for 2005-2009 to 2-5 months for 2010-2014 and 2015-2019. Incidence of SHM was 2.5% in CLL survivors (1736/70,346) with lymphoid SHM being more common than myeloid SHM, and DLBCL being the most common pathology (n = 610, 35% of all SHM). Male sex, age ≤65 years at CLL diagnosis, and chemotherapy treatment were associated with higher risk for SHM. The median gap between CLL and SHM diagnoses was 46 months. The median survival for de-novo-AML, t-MN, CML, and aggressive NHL was 63, 86, 95, and 96 months respectively. Although SHM remains rare, there is increased risk in recent era, likely due to improved survival in CLL patients, necessitating active surveillance strategies.

CSF biomarker concordance with amyloid PET in Phase 3 studies of aducanumab.

INTRODUCTION: We assessed the use of cerebrospinal fluid (CSF) biomarkers as an alternative to positron emission tomography (PET) for brain amyloid beta (Aß) pathology confirmation in the EMERGE and ENGAGE clinical trials. METHODS: EMERGE and ENGAGE were randomized, placebo-controlled, Phase 3 trials of aducanumab in participants with early Alzheimer's disease. Concordance between CSF biomarkers (Aß42, Aß40, phosphorylated tau 181, and total tau) and amyloid PET status (visual read) at screening was examined. RESULTS: Robust concordance between CSF biomarkers and amyloid PET visual status was observed (for Aß42/Aß40, AUC: 0.90; 95% CI: 0.83-0.97; p < 0.0001), confirming CSF biomarkers as a reliable alternative to amyloid PET in these studies. Compared with single CSF biomarkers, CSF biomarker ratios showed better agreement with amyloid PET visual reads, demonstrating high diagnostic accuracy. DISCUSSION: These analyses add to the growing body of evidence supporting CSF biomarkers as reliable alternatives to amyloid PET imaging for brain Aß pathology confirmation. HIGHLIGHTS: CSF biomarkers and amyloid PET concordance were assessed in Ph3 aducanumab trials. Robust concordance between CSF biomarkers and amyloid PET was observed. CSF biomarker ratios increased diagnostic accuracy over single CSF biomarkers. CSF Aß42/Aß40 demonstrated high concordance with amyloid PET. Results support CSF biomarker testing as a reliable alternative to amyloid PET.

Toxicity analysis of busulfan pharmacokinetic therapeutic dose monitoring.

Busulfan-based conditioning regimens are associated with serious toxicities and literature reports increased risk of toxicities when daily area under the curve concentrations exceed 6000 µM-minute. We implemented real time pharmacokinetic-guided therapeutic drug monitoring of busulfan for myeloablative conditioning regimens. The objective was to compare toxicity of intravenous busulfan before and after therapeutic drug monitoring implementation. The primary endpoint was incidence of hepatotoxicity. Medical records were retrospectively reviewed with weight-based dose Busulfan/Cyclophosphamide (BuCy) conditioning from August 2017 through March 2018 (N = 14) and therapeutic drug monitoring from April 2018 through December 2018 (N = 22). Recipients of busulfan therapeutic drug monitoring were younger than those receiving weight-based dose (median: 45 vs. 58 years, p = 0.008). No other baseline differences were observed. There was no difference in hepatotoxicity between therapeutic drug monitoring and weight-based dose (median 1 vs. 0 days, p = 0.40). In the therapeutic drug monitoring group, 45% of patients had increases and 41% had decreases in busulfan dose after Bu1. Repeat pharmacokinetic after Bu2 were required in 32% of patients. A pharmacokinetic dose monitoring program for myeloablative conditioning intravenous busulfan regimens may be considered a safe practice in stem cell transplant recipients. The majority of patients receiving pharmacokinetic-guided therapeutic drug monitoring required dose changes and therapeutic drug monitoring patients had no significant difference in toxicity compared to those receiving weight-based dose.

Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is characterized by amyloid-beta (Aß) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aß, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS: We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer's disease, defined as a Mini-Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aß1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS: A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, -0.80; 95% confidence interval, -1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was -3.17 in the solanezumab group and -3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS: Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665 .).

Posterior Tibial Slope: Understand Bony Morphology to Protect Knee Cruciate Ligament Grafts.

Improved understanding of the biomechanical significance and clinical repercussions of tibial slope on cruciate ligament function has sparked a newfound clinical interest in this morphological feature. Using either magnetic resonance imaging or lateral tibia radiographs, the anterior-posterior angulation of the tibial plateau relative to the tibial shaft can be measured. Clinical and biomechanical studies have reported that increased posterior tibial slope (PTS) places significantly increased tension on the native and reconstructed anterior cruciate ligament (ACL), leading to an increased risk of failure. It has also been suggested that increased PTS of the lateral tibial plateau has a greater impact on ACL forces and anterior tibial translation than PTS of the medial tibial plateau. Conversely, a decreased PTS has been shown to be a risk factor for recurvatum deformity, posterior cruciate ligament (PCL) injury, and posterior tibial translation and has been linked to single bundle PCL reconstruction failure. In the setting of ACL insufficiency with a PTS greater than 12°, anterior closing wedge osteotomy has been shown to be protective for ACL reconstructions. Alternatively, some surgeons have advocated for the addition of lateral extraarticular stabilization procedures in the setting of increased PTS. Further, in the setting of PCL insufficiency with an anteriorly directed, or flat, PTS, anterior opening wedge osteotomy has shown encouraging results. In addition, double bundle PCL reconstructions should be strongly considered in the setting of anteriorly directed, or flat, tibial slope.

Posterior Tibial Slope Measurements Using the Anatomic Axis Are Significantly Increased Compared With Those That Use the Mechanical Axis.

PURPOSE: To compare posterior tibial slope (PTS) measurements from standard lateral knee radiographs with measurements from full-length lateral tibia radiographs. METHODS: We performed a multicenter, prospective study. Lateral knee and full-length lateral tibia radiographs were obtained for each patient, and PTS was measured. Slope measurements were obtained by measuring the angle between an average of the medial and lateral tibial plateaus and a representative tibial diaphysis line. The proximal anatomic axis was measured on lateral knee radiographs, and both the mechanical axis and anatomic axis were measured on full-length lateral tibia radiographs. The mechanical axis was defined as the center of the plateau to the center of the plafond, and the anatomic axis was defined as the center of the tibial diaphysis. The minimal clinically significant difference was defined a priori as 2° of PTS or greater. RESULTS: A total of 140 patients met the inclusion criteria. The average PTS using the proximal anatomic axis was 11.6° ± 3.2° on lateral knee radiographs; the PTS measured on full-length lateral tibia radiographs was 9.5° ± 3.4° using the mechanical axis and 11.8° ± 3.1° using the anatomic axis. There was a significant difference between the measurements with the mechanical axis and both anatomic axis measurements (P < .01) but no significant difference between the 2 anatomic axis measurement techniques (P = .574). In total, 55% of patients (n = 77) had a 2° or greater difference between the proximal anatomic axis and mechanical axis PTS measurement techniques. CONCLUSIONS: There was no significant difference between PTS measurements that used the proximal anatomic axis from lateral knee radiographs and those that used the anatomic axis from full-length lateral tibia radiographs. Thus, lateral knee radiographs are adequate to accurately obtain tibial slope measurements. However, there was a significant difference between PTS measurements that used the anatomic axis and those that used the mechanical axis of the tibia. CLINICAL RELEVANCE: It is recommended that future studies report tibial slope based upon measurements that utilize the anatomic axis in order to ensure that subsequent conclusions are comparable, independent of the radiographic view.

Therapeutic Dose Monitoring of Busulfan Is Associated with Reduced Risk of Relapse in Non-Hodgkin Lymphoma Patients Undergoing Autologous Stem Cell Transplantation.

Optimal administration of busulfan (Bu) is hampered by variable and unpredictable drug metabolism in individual patients. At our institution, Bu was previously administered with fixed weight-based dosing (WBD) in combination with cyclophosphamide (Cy) and etoposide (E) for patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). In 2014, we adopted real-time pharmacokinetic (PK)-guided therapeutic drug monitoring (TDM) of Bu for all NHL patients undergoing Bu-containing ASCT. Here we compare outcomes of NHL patients who underwent ASCT with Bu/Cy/E using WBD and those who did so using TDM of Bu. We studied 336 consecutive adult NHL patients who underwent ASCT with Bu/Cy/E using WBD from January 2007 to December 2013 (n = 258) or TDM from May 2014 to December 2017 (n = 78), excluding patients with mantle cell lymphoma. Clinical outcomes, including relapse, nonrelapse mortality (NRM), progression-free survival (PFS), and overall survival (OS), hepatotoxicity and pulmonary toxicity were compared in the 2 groups. To adjust for differences in baseline characteristics between the groups, propensity-matched cohorts of WBD and TDM patients were also studied. After the first dose of Bu, the dose was increased in 36% of the patients and decreased in 41%. Changes in pulmonary and liver function from baseline to transplantation were not different between the 2 groups, although these changes showed significantly less variability with TDM than with WBD. Relapse was significantly lower and PFS was improved with TDM; 2-year estimates were 19% for TDM and 38% for WBD for relapse (P = .004) and 69% and 55%, respectively, for PFS (P = .038). No significant between-group differences in NRM or OS were seen. In multivariable analysis, TDM remained prognostic for lower risk of relapse (hazard ratio [HR], .52; 95% confidence interval [CI], .30 to .89; P = .018), but did not remain prognostic for PFS (HR, .74; 95% CI, .48 to 1.16; P = .19). Propensity-matched cohorts displayed similar patterns of outcomes. In subset analysis based on disease status at ASCT, TDM was associated with less relapse and better PFS than WBD for patients who underwent transplantation in less than complete remission (CR) compared with those who underwent transplantation in CR. Compared with WBD, PK-directed TDM of Bu reduces the incidence of relapse when used in combination with Cy and E for patients with NHL undergoing ASCT, particularly for patients in less than CR. These data support the continued use of personalized PK-guided dosing for all NHL patients undergoing ASCT with Bu-containing preparative regimens.

Characterisation and prognostic impact of immunoparesis in relapsed multiple myeloma.

Characterisation and prognostic impact of immunoparesis in relapsed multiple myeloma (MM) is lacking in the current literature. We evaluated 258 patients with relapsed MM, diagnosed from 2008 to 2015, to investigate the prognostic impact of deep immunoparesis on post-relapse survival. On qualitative immunoparesis assessment, no, partial and full immunoparesis was present in 9%, 30% and 61% of patients, respectively. Quantitative immunoparesis was assessed by computing the average relative difference (ARD) between polyclonal immunoglobulin(s) and corresponding lower normal limit(s), with greater negative values indicating deeper immunoparesis. The median ARD was -39%, with an optimal cut-off of -50% for overall survival (OS) by recursive partitioning analysis. Deep immunoparesis (ARD ≤-50%) was associated with a higher tumour burden at first relapse compared to none/shallow [ARD >-50%] immunoparesis. The OS (P = 0·007) and progression-free survival (PFS; P < 0·001) differed significantly between the deep and none/shallow immunoparesis groups. Kaplan-Meier estimates for 3-year OS were 36% and 46%, and for 2-year PFS were 17% and 27%, respectively. On multivariable analysis (MVA) for PFS, both qualitative and quantitative immunoparesis retained negative prognostic impact independently. However, only quantitative immunoparesis was independently prognostic for OS on MVA. Depth of immunoparesis in relapsed MM is an important prognostic factor for post-relapse survival in the era of novel agents and continuous therapy.

Diagnostic utility of penile ultrasound in Peyronie's disease.

PURPOSE: To review the literature regarding the use of penile ultrasound in the evaluation and management of Peyronie's disease. METHODS: A literature review was performed using PubMed from 1980 to 2018 using the keywords: Peyronie's disease, ultrasound, sonography, calcification, penile fracture, and penile hematoma. Articles were reviewed for study size, image protocols, and findings. In addition, we reviewed images from 227 penile ultrasounds performed on Peyronie's disease patients at the Walter Reed National Military Medical Center between 2014 and 2018. RESULTS: Through extensive urological and radiographic literature review over the last four decades, common patterns and characteristic of Peyronie's plaques were identified. These characteristics are not always delineated by physical examination alone. The ultrasound images often added objective information including etiology of erectile dysfunction and location or plaques, and presence of calcifications which aid in patient counseling and treatment protocols. CONCLUSIONS: The use of B-mode ultrasound with color Doppler in the evaluation and management of Peyronie's disease is a quick, cost-effective process that provides objective information that can assist the urologist in the treatment of patients with Peyronie's disease.

The Influence of Physeal Status on Rate of Reoperation After Arthroscopic Screw Fixation for Symptomatic Osteochondritis Dissecans of the Knee.

PURPOSE: To determine if physeal status or other preoperative or intraoperative variables influence the failure rate after arthroscopic reduction and internal fixation of osteochondritis dissecans (OCD) lesions in the knee. METHODS: Consecutive patients undergoing screw fixation of osteochondral fragments from OCD by a single surgeon from 2005 to 2015 with a minimum 2-year follow-up were included. Demographic, preoperative imaging, and intraoperative data were analyzed to determine risk factors associated with failure, which was defined as the need for a revision reoperation or arthroplasty after initial OCD fixation. RESULTS: A total of 45 knees met the inclusion criteria, including 26 skeletally mature patients and 19 patients with incompletely closed physes on preoperative imaging. The mean ages of the skeletally mature and immature groups were 18.3 ± 2.5 years and 14.9 ± 2.2 years, respectively (P < .001), and the mean body mass index values were 24.3 ± 3.6 and 23.2 ± 4.0, respectively (P = .432). We excluded 10 patients from the survivorship analysis because they had less than 2 years' follow-up. No statistically significant difference in failure rates was found between skeletally mature and immature individuals (30% and 40%, respectively; P = .721). The only factor significantly associated with fixation failure was undergoing a prior surgical procedure to address the OCD lesion (P = .038). Kaplan-Meier analysis showed rates of overall survivorship from revision reoperations of 88.6% at 1 year and 68.8% at 5 years. CONCLUSIONS: Outcomes after internal fixation of OCD fragments are guarded, with a fragment survival rate of 65.7% at a mean of 4.1 years' follow-up. No difference in fragment survival was noted in skeletally mature versus immature patients. The only independent risk factor identified for fixation failure was the number of previous operations. LEVEL OF EVIDENCE: Level IV, case series with subgroup analysis.

Conditional Long-Term Survival after Autologous Hematopoietic Cell Transplantation for Diffuse Large B Cell Lymphoma.

Autologous hematopoietic cell transplantation (AHCT) is standard therapy for patients with chemosensitive, relapsed, diffuse large B cell lymphoma (DLBCL). We performed a retrospective cohort study to delineate subsequent (conditional) and relative survival in 371 adult patients with DLBCL who underwent AHCT between 2000 and 2014 and had survived for 1, 2, 3, or 5 years after transplant. The probability of overall survival at 10 years after AHCT was 62%, 71%, 77%, and 86%, respectively, for the 4 cohorts, whereas that of progression-free survival (PFS) was 55%, 65%, 72%, and 81%, respectively. The respective cumulative incidence of nonrelapse mortality (NRM) at 10 years after transplantation was 13%, 12%, 11%, and 8%, respectively. In multivariable analysis, older age was associated with greater mortality risk among all but 5-year survivors; relapse within the landmark time was associated with greater mortality risk in all groups. Older age and relapse within the landmark time were associated with worse PFS in all groups. Standardized mortality ratio (SMR) was significantly higher than an age-, gender-, and race-matched general population, with the magnitude of SMR decreasing as the landmark time increased (4.0 for 1-year, 3.0 for 2-year, 2.4 for 3-year, and 1.8 for 5-year survivors). Our study provides information on long-term survival and prognosis that will assist in counseling patients with DLBCL who have received AHCT. Survival improves with longer time in remission post-transplant, although patients continue to remain at risk for NRM, underscoring the need for continued vigilance and prevention of late complications.

BEAM versus BUCYVP16 Conditioning before Autologous Hematopoietic Stem Cell Transplant in Patients with Hodgkin Lymphoma.

High-dose chemotherapy followed by autologous hematopoietic stem cell transplant (AHSCT) is a standard of care for patients with relapsed Hodgkin lymphoma. Different conditioning regimens before AHSCT have been used, with the 2 most common being BEAM (carmustine, etoposide, cytarabine, and melphalan) and BUCYVP16 (busulfan, cyclophosphamide, and etoposide). We retrospectively compared the outcomes of patients treated with BEAM (n = 128) or BUCYVP16 (n = 105) followed by AHSCT. After a median follow-up of 4.2 years for BEAM and 3.8 for BUCYVP16 from AHSCT, the 5-year cumulative incidence of relapse was 29% with BEAM compared with 56% with BUCYVP16 (P < .001). Median progression free survival (PFS) and overall survival (OS) were not reached with BEAM and were 2.0 and 7.8 years with BUCYVP16, respectively. Improved PFS (P < .001) and OS (P = .001) were observed with BEAM for patients who needed transplant within 24 months from diagnosis and for patients not in complete remission (non-CR; P = .001 and P < .001, respectively) at AHSCT. In this large retrospective comparison the use of BEAM conditioning before AHSCT resulted in a statistically significant improved PFS and OS and lower relapse compared with BUCYVP16. This supports the use of BEAM as a frontline conditioning regimen before AHSCT for early relapsed and non-CR Hodgkin lymphoma.

Progression with clinical features is associated with worse subsequent survival in multiple myeloma.

Response rate and survival in multiple myeloma (MM) has improved in the era of proteasome inhibitors and immunomodulatory drugs. However, most patients eventually relapse with biochemical progression (BP) alone or with clinical features of end-organ damage (CP: clinical progression), without or without extramedullary (EM) disease. We conducted a retrospective cohort study of 252 patients with MM experiencing first relapse (time, T0 ) to evaluate survival following CP with and without EM as a function of BP. Patients were divided into three groups: BP (n = 134; 53%), CP/EM- (n = 87; 35%) and CP/EM+ (n = 31; 12%). The median time from diagnosis to T0 was significantly shorter in CP/EM+ compared to CP/EM- and BP groups (13 vs 25 vs 25 months; P < 0.001). The incidence of abnormal metaphase cytogenetics at diagnosis was significantly higher in CP/EM+ compared to CP/EM- and BP groups (46% vs 18% vs 11% respectively; P < 0.001). At a median follow-up of 26 months from T0 , median overall survival was 50, 19 and 10 months for BP, CP/EM- and CP/EM+ groups, respectively (P < 0.001). On multivariable analysis, pattern of progression was a significant prognostic factor for OS (HR for CP/EM- vs BP: 3.6; CP/EM+ vs BP: 8.7 and CP/EM+ vs CP/EM-: 2.42; P < 0.001 for all comparisons), along with age at T0 . In conclusion, progression pattern is an important prognostic factor in the current era, with subsequent survival being dismal in patients with end-organ damage or EM disease at relapse. Clinical trials in relapsed MM should consider reporting patterns of progression at baseline to ensure balance between study arms.

Early infectious complications after autologous hematopoietic cell transplantation for multiple myeloma.

BACKGROUND: The spectrum of infectious complications in autologous hematopoietic cell transplant recipients (AHCT) with multiple myeloma has not been well described in the recent era of novel agent induction and improved supportive care. METHODS: We conducted a retrospective cohort study of 413 adult myeloma AHCT recipients at our institution from 2007-2016 to describe the cumulative incidence and risk factors for various infections and FN occurring within the first 100 days after AHCT. Additionally, landmark analysis was done among 404 patients who survived at least 100 days after transplant admission to estimate the association of infections with subsequent non-relapse mortality (NRM), overall survival (OS), and relapse-free survival (RFS). RESULTS: Cumulative incidences (95% CI) of infection events by day 100 were: FN 43% (38-48), any infection 21% (17-25), bacterial 17% (14-21), viral 4% (3-7) and fungal 1% (0.5-3), central line-associated blood stream infection 3% (2-6), and Clostridium difficile colitis 6% (4-8). Patients with infection had a longer initial transplant hospitalization (median 17 vs 16 days, P < 0.01), more readmissions (31% vs 8%, P < 0.01), and spent more days in hospital in first 100 days (median 18 vs 16 days, P < 0.01). A 100-day mortality was low and similar between groups (2% vs 1%, P = 0.28). In landmark analysis of 404 100-day survivors, OS was worse among patients with early infections (hazard ratio 1.54 [1.03-2.30], P = 0.03), although there was no difference in NRM and RFS. CONCLUSIONS: Notwithstanding advances in supportive care, early infectious complications remain a relevant source of morbidity and require attention in myeloma AHCT recipients.

Adaptation of the robust method to large distributions of reference values: program modifications and comparison of alternative computational methods.

The objective of this research was to compute reference limits using reference values from patients entering pharmaceutical development clinical trials by the nonparametric method and the robust method of Horn and Pesce, with and without outlier exclusion, and compare the methods with respect to influence on the limits. Reference limits were computed for 38 analytes with over 130,000 subjects contributing reference values. Subjects were partitioned into 10 demographic strata for limit computation. Limits were computed for both 95- and 98-percentile reference intervals by both methods. For each reference interval and method, the limits were calculated with and without outliers. Outliers were excluded by the Horn algorithm. Irrespective of method, reference limits were expanded with the 98-percentile interval, but some expansions were small. Outlier exclusion contracted limits with more influence on the upper limit. The robust method contracted the upper limit to a meaningful degree and slightly expanded the lower limit for many analytes. Outlier exclusion and computation by the robust method have an increasing influence on analytes with right-skewed distributions of reference values from large populations not screened to exclude common, stable diseases and environmental factors that might affect analyte variability. The method has advantages for computation of reference limits used in clinical trial analyses.

Body mass index does not impact hematopoietic progenitor cell mobilization for autologous hematopoietic cell transplantation.

BACKGROUND: Obesity has implications for hematopoietic progenitor cell (HPC) mobilization, chemotherapy administration, and medication dosing. We analyzed the impact of obesity on HPC mobilization as well as key outcomes that are associated with cell dose in autologous hematopoietic cell transplantation (AHCT) recipients. METHODS: We conducted a retrospective cohort study on 556 consecutive eligible AHCT recipients at our institution from 1/2004 to 12/2009. Patients were categorized into four groups based on the body mass index (BMI): underweight (BMI < 18.5), normal (18.5-24.9), overweight (25.0-29.9), or obese (≥30.0). Primary endpoints of interest included HPC mobilization, neutrophil and platelet recovery, hospital stay and survival. RESULTS: The diagnoses were mostly non-Hodgkin lymphoma, multiple myeloma, and Hodgkin lymphoma. The majority of the patients had received three or less prior chemotherapy regimens and had not received prior radiation therapy. Most patients had chemosensitive disease at time of transplant. For HPC mobilization regimen, 68% received chemotherapy and G-CSF, 32% received G-CSF alone. Busuflan/etoposide/cyclophosphamide, melphalan, and busulfan/cyclophosphamide were used for conditioning. Obesity did not correlate with HPC mobilization and had no association with neutrophil or platelet recovery, or length of transplant hospitalization. On multivariable analysis, obese patients demonstrated better survival than those who were not obese. CONCLUSION: Obese AHCT recipients had similar rates of HPC mobilization, neutrophil and platelet engraftment and length of transplant hospitalization, and experienced better survival compared with recipients with lower BMI. High BMI by itself should not be considered as a contraindication to AHCT.