Trends in Outcomes After Upfront Autologous Transplant for Multiple Myeloma Over Three Decades.

Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 1988-2000 (n = 249), 2001-2005 (n = 373), 2006-2010 (n = 568), 2011-2015 (n = 815) and 2016-2021 (n = 1036). High-risk cytogenetic abnormalities were defined as del (17p), t (4;14), t (14;16), and 1q21 gain or amplification by fluorescence in situ hybridization. We included 3041 MM patients in the analysis. Median age at auto-SCT increased from 52 years (1988-2000) to 62 years (2016-2021), as did the incidence of high-risk cytogenetics from 15% to 40% (P < .001). Comorbidity burden, as measured by a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) of >3, increased from 17% (1988-2000) to 28% (2016-2021) (P < .001). Induction regimens evolved from predominantly chemotherapy to immunomodulatory drug (IMiD) and proteasome inhibitor (PI) based regimens, with 74% of patients receiving IMiD-PI triplets in 2016-2021 (39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone [KRD]). Response rates prior to auto-SCT steadily increased, with 4% and 10% achieving a ≥CR and ≥VGPR compared to 19% and 65% between 1988-2000 and 2016-2021, respectively. Day 100 response rates post auto-SCT improved from 24% and 49% achieving ≥CR and ≥VGPR between 1988-2000 to 41% and 81% between 2016-2021, respectively. Median PFS improved from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (HR 0.42, P < .001). Among patients with high-risk cytogenetics, median PFS increased from 13.7 months to 36.8 months (HR 0.32, P < .001). Patients aged ≥65 years also had an improvement in median PFS from 33.6 months between 2001 and 2005 to 52.8 months between 2016-2021 (HR 0.56, P = .001). Median OS improved from 55.1 months between 1988-2000 to not reached (HR 0.41, P < .001). Patients with high-risk cytogenetics had an improvement in median OS from 32.9 months to 66.5 months between 2016-2021 (HR 0.39, P < .001). Day 100 non-relapse mortality from 2001 onwards was ≤1%. Age-adjust rates of second primary malignancies were similar in patients transplanted in different time periods. Despite increasing patient age and comorbidity burden, this large real-world study demonstrated significant improvements in the depth of response and survival outcomes in patients with NDMM undergoing upfront auto-SCT over the past three decades, including those with high-risk disease.

Incidence and risk factors of early onset VOD/SOS differ in younger vs older adults after stem cell transplantation.

ABSTRACT: Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Although increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with posttransplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single-center analysis of adult patients aged ≥18 years undergoing allo-SCT (N = 1561) using predominately PTCy as graft-versus-host disease (GVHD) prophylaxis (72%). We found a higher rate of VOD at 16.8% (20 of 119) in those aged ≤25 years compared with 3.8% (55 of 1442) in those aged >25 years, with unique predictors of VOD within each cohort. Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD. Among patients aged 18 to 25 years, disease risk index (DRI; 31% with high/very high DRI vs 12% low/intermediate DRI; P = .03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1; P = .03) were the strongest predictors of VOD. Incidence of VOD in patients aged >25 years of age consistently ranged between 3% and 5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase, alanine aminotransferase) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared with those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors of VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.

Upfront allogeneic transplantation versus JAK inhibitor therapy for patients with myelofibrosis: a North American collaborative study.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF) and is recommended for patients with higher risk disease. However, there is a risk of early mortality, and optimal timing is unknown. JAK inhibitor (JAKi) therapy may offer durable improvement in symptoms, splenomegaly and quality of life. The aim of this multicentre, retrospective observational study was to compare outcomes of patients aged 70 years or below with MF in chronic phase who received upfront JAKi therapy vs. upfront HCT in dynamic international prognostic scoring system (DIPSS)-stratified categories. For the whole study cohort, median overall survival (OS) was longer for patients who received a JAKi vs. upfront HCT, 69 (95% CI 57-89) vs. 42 (95% CI 20-not reached, NR) months, respectively (p = 0.01). In patients with intermediate-2 and high-risk disease, median OS was 55 (95% CI 36-73) months with JAKi vs. 36 (95% CI 20-NR) months for HCT (p = 0.27). An upfront HCT strategy was associated with early mortality and difference in median OS was not observed in any risk group by 5 years of follow-up. Within the limitations of a retrospective observational study, we did not observe any benefit of a universal upfront HCT approach for higher-risk MF.

Outcomes of young adults (aged ≤ 40 years) with newly diagnosed multiple myeloma after up-front autologous stem cell transplant.

Multiple myeloma (MM) primarily affects older patients. There are scarce data on the outcomes of young adults undergoing autologous transplantation (auto-HCT). In this single-centre analysis, we included 117 younger patients, with a median age of 37 years (range 22-40) at transplant. Seventeen (15%) patients had high-risk cytogenetics. Before transplant, 10% of patients achieved ≥CR and 44% achieved ≥VGPR. At best post-transplant response, 56% and 77% of patients achieved ≥CR and ≥VGPR respectively. With a median follow-up for survivors of 72.6 months (range 0.9-238.0), median PFS and OS were 43.1 months (95% CI 31.2-65.0) and 146.6 months (95% CI 100.0-208.1) respectively. Patients who underwent auto-HCT after 2010 had better median PFS (84.9 months vs. 28.2 months, p < 0.001) and OS (NR vs. 91.8 months, p < 0.001) compared with those transplanted earlier. In multi-variate analysis, achieving ≥CR as best post-transplant response was associated with improved PFS (HR [95% CI] 0.55 [0.32-0.95], p = 0.032), while achieving ≥VGPR was predictive of superior OS (0.32 [0.16-0.62], p < 0.001). Three patients (3%) developed a second primary malignancy. Younger MM patients had durable survival after auto-HCT, which further improved after the availability of novel anti-myeloma drugs in recent years. Depth of response following transplant remains a key predictor of survival.

Younger haploidentical donor versus older matched unrelated donor for patients with AML/MDS.

Optimal donor selection is fundamental to successful allogeneic hematopoietic cell transplantation (HCT), and donor age influences survival after both matched unrelated donor (MUD) and haploidentical donor HCT. Though recent studies have shown similar outcomes between MUD and haploidentical HCT, it is unknown if outcomes differ following HCT with younger haploidentical donors compared to HCT with older MUDs. Therefore, we performed a retrospective analysis comparing outcomes of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients who underwent HCT with younger (≤35 years) haploidentical donors (n = 494) or older (>35 years) MUDs (n = 1005). Patients in the haploidentical and MUD groups received post-transplant cyclophosphamide (PTCy) and conventional graft-versus-host-disease (GVHD) prophylaxis, respectively. In multivariate analysis, use of younger haploidentical donors was associated with improved overall survival (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.69-0.95, p = .01) and lower rates of grade II-IV acute GVHD (HR 0.64, 95% CI 0.53-0.77, p < .001), grade III-IV acute GVHD (HR 0.37, 95% CI 0.25-0.53, p < .001), and chronic GVHD (HR 0.49, 95% CI 0.40-0.60, p < .001). Relapse rates were similar among those who received myeloablative conditioning but were higher in patients of the younger haploidentical group who received reduced intensity conditioning (HR 1.49, 95%CI 1.18-1.88, p = .001). The younger haploidentical group had significantly lower non-relapse mortality ≥3 months post-HCT (HR 0.59, 95% CI 0.38-0.90, p = .02). Our data support the use of younger haploidentical donors with PTCy over older MUDs with conventional prophylaxis in patients with MDS or AML. Further studies on the importance of donor age in haploidentical and MUD HCT with PTCy prophylaxis are warranted.

HLA Factors versus Non-HLA Factors for Haploidentical Donor Selection.

When multiple haploidentical donors are available for transplantation, those of younger generations are generally selected over those of older generations. However, it is unclear who is the optimal donor when selecting candidates from within a generation, such as father versus mother, son versus daughter, or brother versus sister. Although traditionally male donors are favored over female donors, particularly for male recipients, and significant associations of individual HLA mis(matches) on outcomes are being increasingly recognized, the hierarchy of factors for donor selection is indeterminate. To assess whether HLA factors take precedence over non-HLA factors and to isolate the influence of specific characteristics on outcomes, we analyzed 412 patients stratified by donor relationship: child donor (son [n = 202] versus daughter [n = 96]), parent (father [n = 28] versus mother [n = 29]), and sibling (noninherited maternal [NIMA; n = 29] versus paternal [NIPA; n = 28] mismatched). Among siblings, NIMA mismatch was associated with a lower risk of acute graft-versus-host disease (aGVHD); B-leader mismatch was associated with high nonrelapse mortality (NRM), poor progression-free survival, and a trend toward poor overall survival (OS), whereas A-mismatch was associated with lower aGVHD. Among parent donors, the relationship did not impact any outcome; B-leader mismatch was associated with higher NRM and a trend toward poor OS, whereas A-mismatch was associated with lower NRM and improved progression-free survival and OS. Among child donors, no individual HLA mismatch was predictive of any outcome, and daughter donors were not associated with any adverse outcomes in multivariate analyses. Our data suggest that certain HLA factors may be more significant in some cases and should be given priority over simply selecting a donor based on relationship/sex.

Prospective Assessment of an Automated Intraprocedural 12-Lead ECG-Based System for Localization of Early Left Ventricular Activation.

BACKGROUND: To facilitate ablation of ventricular tachycardia (VT), an automated localization system to identify the site of origin of left ventricular activation in real time using the 12-lead ECG was developed. The objective of this study was to prospectively assess its accuracy. METHODS: The automated site of origin localization system consists of 3 steps: (1) localization of ventricular segment based on population templates, (2) population-based localization within a segment, and (3) patient-specific site localization. Localization error was assessed by the distance between the known reference site and the estimated site. RESULTS: In 19 patients undergoing 21 catheter ablation procedures of scar-related VT, site of origin localization accuracy was estimated using 552 left ventricular endocardial pacing sites pooled together and 25 VT-exit sites identified by contact mapping. For the 25 VT-exit sites, localization error of the population-based localization steps was within 10 mm. Patient-specific site localization achieved accuracy of within 3.5 mm after including up to 11 pacing (training) sites. Using 3 remotes (67.8±17.0 mm from the reference VT-exit site), and then 5 close pacing sites, resulted in localization error of 7.2±4.1 mm for the 25 identified VT-exit sites. In 2 emulated clinical procedure with 2 induced VTs, the site of origin localization system achieved accuracy within 4 mm. CONCLUSIONS: In this prospective validation study, the automated localization system achieved estimated accuracy within 10 mm and could thus provide clinical utility.

Annual colonoscopy volume and maintenance of competency for surgeons.

INTRODUCTION: To determine whether the annual case volume of general surgeons (greater or less than 200 colonoscopies) is associated with quality outcomes. METHODS: This retrospective cohort study involved all adults who underwent colonoscopy by a surgeon in the city of St. John's, NL, during the first 6 months of 2012. Subjects were identified through records from the health authority, and data were recorded on a standardized data sheet. Univariate analysis followed by stepwise multivariable logistic regression was performed to determine whether there was an association between quality outcomes (colonoscopy completion rate, adenoma detection rate) and predictors of these outcomes including annual colonoscopy volume, patient age, gender, indication for colonoscopy, and ASA score. A Chi-squared test was used to determine whether other outcomes were associated with annual colonoscopy volume. RESULTS: Data were collected on 1060 patients. Mean age was 59.5 (sd 12.2) years with 550 females. A total of 13 surgeons were studied, of which 7 performed less than 200 annual colonoscopies over the previous 2 years (low-volume group) and 6 performed more than 200 annual colonoscopies over the previous 2 years (high-volume group). While there was a significant difference in the colonoscopy completion rate favoring the high-volume group (82.2 vs. 91.1 %, p < 0.001), no difference was noted in the adenoma detection rate between groups (16.7 vs. 17.7 %, p = 0.762). The regression model revealed that colonoscopy completion was also associated with an indication of screening or surveillance and an ASA score of 1 or 2. The adenoma detection rate was associated with older age and male gender. There was no statistically significant association between annual colonoscopy volume and other safety outcome measures. CONCLUSION: Performing over 200 colonoscopies annually is associated with higher colonoscopy completion rates, but does not appear to be associated with other quality measures.

Effect of Colonoscopy Volume on Quality Indicators.

Background. The purpose of this study is to determine if colonoscopy quality is associated with the annual case volume of endoscopists. Methods. A retrospective cohort study was performed on 3235 patients who underwent colonoscopy in the city of St. John's, NL, between January and June 2012. Data collected included completion of colonoscopy (CCR) and adenoma detection rates (ADR). Endoscopists were divided into quintiles based on annual case volume. To account for potential confounding variables, univariate analyses followed by multivariable logistic regression were used to identify variables independently associated with CCR and ADR. Results. A total of 13 surgeons and 8 gastroenterologists were studied. There was a significant difference in CCR (p < 0.001) and ADR (p < 0.001) based on annual volume. Following multivariable regression, predictors of successful colonoscopy completion included annual colonoscopy volume, lower age, male sex, an indication of screening or surveillance, and a low ASA score. Predictors of adenoma detection included older age, male sex, an indication of screening or surveillance, and gastroenterology specialty. Conclusion. Higher annual case volume is associated with better quality of colonoscopy in terms of completion. However, gastroenterology specialty appears to be a better predictor of ADR than annual case volume.

Canadian Association of Gastroenterology Indicators of Safety Compromise following Colonoscopy in Clinical Practice.

In 2012 the Canadian Association of Gastroenterology published 19 indicators of safety compromise. We studied the incidence of these indicators by reviewing all colonoscopies performed in St. John's, NL, between January 1, 2012, and June 30, 2012. Results. A total of 3235 colonoscopies were included. Adverse events are as follows. Medication-related includes use of reversal agents 0.1%, hypoxia 9.9%, hypotension 15.4%, and hypertension 0.9%. No patients required CPR or experienced allergic reactions or laryngospasm/bronchospasm. The indicator, "sedation dosages in patients older than 70," showed lower usage of fentanyl and midazolam in elderly patients. Procedure-related immediate includes perforation 0.2%, immediate postpolypectomy bleeding 0.3%, need for hospital admission or transfer to the emergency department 0.1%, and severe persistent abdominal pain proven not to be perforation 0.4%. Instrument impaction was not seen. Procedure-related delayed includes death within 14 days 0.1%, unplanned health care visit within 14 days of the colonoscopy 1.8%, unplanned hospitalization within 14 days of the colonoscopy 0.6%, bleeding within 14 days of colonoscopy 0.2%, infection 0.03%, and metabolic complication 0.03%. Conclusions. The most common adverse events were mild and sedation related. Rates of serious adverse events were in keeping with published reports.

Balanced ionotropic receptor dynamics support signal estimation via voltage-dependent membrane noise.

Encoding behaviorally relevant stimuli in a noisy background is critical for animals to survive in their natural environment. We identify core biophysical and synaptic mechanisms that permit the encoding of low-frequency signals in pyramidal neurons of the weakly electric fish Apteronotus leptorhynchus, an animal that can accurately encode even miniscule amplitude modulations of its self-generated electric field. We demonstrate that slow NMDA receptor (NMDA-R)-mediated excitatory postsynaptic potentials (EPSPs) are able to summate over many interspike intervals (ISIs) of the primary electrosensory afferents (EAs), effectively eliminating the baseline EA ISI correlations from the pyramidal cell input. Together with a dynamic balance of NMDA-R and GABA-A-R currents, this permits stimulus-evoked changes in EA spiking to be transmitted efficiently to target electrosensory lobe (ELL) pyramidal cells, for encoding low-frequency signals. Interestingly, AMPA-R activity is depressed and appears to play a negligible role in the generation of action potentials. Instead, we hypothesize that cell-intrinsic voltage-dependent membrane noise supports the encoding of perithreshold sensory input; this noise drives a significant proportion of pyramidal cell spikes. Together, these mechanisms may be sufficient for the ELL to encode signals near the threshold of behavioral detection.

Does the hands-on, technical training of residents in colonoscopy affect quality outcomes?

INTRODUCTION: The training of residents in colonoscopy has become an important topic as more attention is being paid to quality outcomes. PURPOSE: To determine whether colonoscopy quality outcomes are adversely affected by allowing residents to perform colonoscopies under supervision. METHODS: This retrospective cohort study was performed on all adults who underwent colonoscopy in the city of St. John's, NL, from January to June 2012 by an endoscopist who trains residents. Subjects were identified through records from the health authority. Data were extracted from the electronic medical record, including the endoscopy procedure report, the nursing record of the endoscopy, and the pathology report. Data were recorded on a standardized data sheet and entered into SPSS version 19.0 for analysis. A Chi-squared test was used for categorical data and a t test was used for continuous data. RESULTS: A total of 867 cases involving seven endoscopists and three trainees were studied. The colonoscopy was performed by an endoscopist in 673 cases and performed by a trainee in 194 cases. Mean age [59.3 (SD 12.44) years] and gender (51.7% female) were similar between groups. There was no difference in cecal intubation rate (90.6 vs. 89.2%, p = 0.544) between endoscopists and trainees. There was a difference in polyp detection (23.3 vs. 33.5%, p = 0.004) and adenoma detection (12.8 vs. 22.7%, p = 0.034) favoring the trainees. There was no difference in the average dose of Fentanyl given (98.4 vs. 94.9 mg, p = 0.066), but there was less use of Versed favoring the trainee group (3.59 vs. 3.31 mg, p = 0.002). There was no difference in the endoscopy nurses' perception of patient discomfort between groups (28.7 vs. 26.7%, p = 0.632). CONCLUSION: The presence of a trainee does not appear to adversely affect quality outcomes in colonoscopy. When the polyp and adenoma detection rates of endoscopists are low, the addition of a trainee may improve these detection rates.