Sharma, Mayank

AbstractBackgroundIt is suggested that patients with defecation disorders (DD) strain excessively or do a Valsalva maneuver (VM) during evacuation, resulting in rectoanal discoordination, which hinders rectal evacuation. However, definitive data are lacking.MethodsRectoanal pressures during evacuation and a VM were measured with seated high‐resolution manometry (HRM) in 64 healthy and 136 constipated women with a normal (84 women, C‐normal) or prolonged (52 women, C‐abnormal) balloon expulsion time (BET). The number of abnormal rectoanal parameters during evacuation and the joint distribution of pressures during evacuation and a VM were used to discriminate between controls and C‐abnormal BET patients.Key ResultsThe peak anal pressure (5 s) during a VM accounted for 0%, 26%, and 49% of the variance in anal pressure during evacuation in healthy women, C‐normal BET, and C‐abnormal BET. The association between anal pressure during a VM and evacuation was stronger in C‐abnormal BET than in healthy women and C‐normal BET (p for interaction <0.001). Fifty‐eight of 64 controls and 33 of 52 C‐abnormal BET patients had no or one abnormal parameter during evacuation; hence, the probability of C‐abnormal BET was 33/91 (36%). In patients with no or one abnormal parameter during evacuation, a logistic model based on anal pressures during evacuation and a VM discriminated between controls and patients with C‐abnormal BET with a sensitivity and a specificity of 67% and 75%.ConclusionsAssessment of rectoanal pressures during evacuation and a VM uncovers rectaoanal discoordination and facilitates the diagnosis of DD in selected patients.

Hindered by a limited understanding of the mechanisms responsible for diabetic gastroenteropathy (DGE), management is symptomatic. We investigated the duodenal mucosal expression of protein-coding genes and microRNAs (miRNA) in DGE and related them to clinical features. The diabetic phenotype, gastric emptying, mRNA, and miRNA expression and ultrastructure of duodenal mucosal biopsies were compared in 39 DGE patients and 21 controls. Among 3175 differentially expressed genes (FDR < 0.05), several mitochondrial DNA–encoded (mtDNA-encoded) genes (12 of 13 protein coding genes involved in oxidative phosphorylation [OXPHOS], both rRNAs and 9 of 22 transfer RNAs) were downregulated; conversely, nuclear DNA–encoded (nDNA-encoded) mitochondrial genes (OXPHOS) were upregulated in DGE. The promoters of differentially expressed genes were enriched in motifs for transcription factors (e.g., NRF1), which regulate mitochondrial biogenesis. Seventeen of 30 differentially expressed miRNAs targeted differentially expressed mitochondrial genes. Mitochondrial density was reduced and correlated with expression of 9 mtDNA OXPHOS genes. Uncovered by principal component (PC) analysis of 70 OXPHOS genes, PC1 was associated with neuropathy ( P = 0.01) and delayed gastric emptying ( P < 0.05). In DGE, mtDNA- and nDNA-encoded mitochondrial genes are reduced and increased — associated with reduced mitochondrial density, neuropathy, and delayed gastric emptying — and correlated with cognate miRNAs. These findings suggest that mitochondrial disturbances may contribute to delayed gastric emptying in DGE.

AbstractBackgroundThe equipment and methods for performing anorectal manometry and biofeedback therapy are different and not standardized. Normal values are influenced by age and sex. Our aims were to generate reference values, examine effects of gender and age, and compare anorectal pressures measured with diagnostic and biofeedback catheters and a portable manometry system.MethodsIn this multicenter study, anorectal pressures at rest, during squeeze, and evacuation were measured with diagnostic and biofeedback catheters using Mcompass™ portable device in healthy subjects. Balloon expulsion time and rectal sensation were evaluated. The effects of age and gender were assessed.ResultsThe final dataset comprised 108 (74 women) of 124 participants with normal rectal balloon expulsion time (less than 60 s). During squeeze, anal resting pressure increased by approximately twofold in women and threefold in men. During evacuation, anal pressure exceeded rectal pressure in 87 participants (diagnostic catheter). The specific rectoanal pressures (e.g., resting pressure) were significantly correlated and not different between diagnostic and biofeedback catheters. With the diagnostic catheter, the anal squeeze pressure and rectal pressure during evacuation were greater in men than women (p ≤ 0.02). Among women, women aged 50 years and older had lower anal resting pressure; rectal pressure and the rectoanal gradient during evacuation were greater in older than younger women (p ≤ 0.01).ConclusionsAnal and rectal pressures measured with diagnostic and biofeedback manometry catheters were correlated and not significantly different. Pressures were influenced by age and sex, providing reference values in men and women.

AbstractObjectivesDefecation requires relaxation of the internal and external anal sphincters. High anal resting pressure is associated with painful constipation, defecatory disorders, and increased healthcare utilization in constipated patients; the mechanisms are unclear. Perhaps patients with a high anal resting pressure have a less distensible canal, which impedes defecation.MethodsIn 50 of 64 participants (33 healthy and 17 constipated women), anal pressures and distensibility were measured, respectively, with manometry and balloon distention combined with magnetic resonance imaging; rectal balloon expulsion time (BET) was also studied.ResultsThe BET (P = .006) was longer, and the mean (SD) rectoanal pressure gradient (−58[40] vs −34[26] mm Hg,P = .03) was more negative in constipated than healthy women; anal resting pressure was not different. During anal distention, the balloon expanded rapidly at an opening pressure of 49 (18) mm Hg, which was lower (P < .0001) than resting pressure (90 [25] mm Hg). The resting pressure was correlated with the opening pressure (r = 0.57,P < .0001) and inversely (r = −0.38,P = .007) with maximum volume but not with anal distensibility (volume‐pressure slope). In healthy women, the difference (opening‐resting pressure) was correlated with anal relaxation during evacuation (r = 0.35,P = .04). Anal distensibility and sensory thresholds were not different between constipated and healthy women.ConclusionsAmong healthy and constipated women, a greater anal resting pressure is correlated with greater opening pressure and lower maximum volume during distention, and, hence, provides a surrogate marker of anal distensibility. The difference (opening‐resting pressure), which reflects anal relaxation during distention, is correlated with anal relaxation during evacuation. Anal resting pressure and distensibility were comparable in healthy and constipated women.

AbstractBackgroundWe compared the utility of existing and modified versions of high‐resolution manometry for diagnosing defecatory disorders (DD).MethodsIn 64 healthy and 136 constipated women, we compared left lateral (LL) and seated manometry, and analyzed with existing (ManoView™) and new methods, for discriminating between constipated patients with normal and prolonged rectal balloon expulsion time (BET). In both positions, the rectoanal gradient (RAG) and, for the new analysis, the pressure topography pattern during evacuation were used to discriminate between constipated patients without and with DD.Key ResultsThe BET was prolonged, suggestive of a DD, in 52 patients (38%). During evacuation, rectoanal pressures and the RAG were greater in the seated than the LL position (P≤.001). The new analysis identified 4 rectoanal pressure patterns. In the seated position, the BET was associated with the pattern (P=.0001), being prolonged in, respectively, 45%, 15%, 53%, and 0% of patients with minimal change, anal relaxation, paradoxical contraction, and transmission. Within each pattern, the RAG was greater (ie, less negative, P<.0001) in patients with a normal than a prolonged BET. Compared to the ManoView™ RAG in the LL position, the integrated analysis (ie, pattern and new RAG) in the LL position (P<.01) and the seated ManoView™ gradient (P=.02) were more effective for discriminating between constipated patients without and with DD.Conclusions & InferencesAnorectal HRM ideally should be performed in the more physiological seated position and analyzed by a two‐tier approach, which incorporates the overall pattern followed by the rectoanal gradient. These findings reinforce the utility of manometry for diagnosing DD.

Abstract Background: Disparities in MM survival among different racial groups persist despite improvements in overall survival (OS). We report a comprehensive review of the SEER Medicare database to elucidate the causes of differences in disease presentation, management practices, cost of care and their relationships to outcomes among the MM patients (pts) from different racial groups. Methods: Pts diagnosed with MM between 1991-2010 with continuous Medicare coverage (1 year prior to diagnosis-date of death/end of 2012) were included. MM complications (MM-C); hypercalcemia (C), renal dysfunction (R), anemia (An), bone fractures (B), dialysis (D) occurring prior to/within 30 days of MM diagnosis (at diagnosis; AT-D), or any time later (after diagnosis; AF-D) were summarized. Demographics, survival (PEDSAF files) and disease characteristics, drug/stem cell transplant (SCT) utilization (NCH, OUTSAF, PDESAF files) were obtained. Trends in incidence of MM-C, treatment type over time (proportional odds) and their association with race (logistic regressions) were compared. Associations between race, MM-C AT-D and MM related death using Fine and Gray's competing risk methods were analyzed. Medicare claims adjusted for inflation (2013) within the first 6 months (mth)/total MM care were summed by drug and total charges. Median cost of care by race and year of diagnosis were evaluated by Kruskal-Wallis (univariate) and proportional odds models (multivariate). Results: A total of 35842 pts (52.1% males) with median age of 76 yr (range 18-104) were included. Mutually exclusive racial subgroups were: White (W, 72%), Hispanic (H: 7.3%), African-American (AA, 16.2%), Asian (A, 4.1%), other (0.3%). A significantly increasing trend in the prevalence of all MM-C AT-D was seen over time (all p<0.001). For AF-D, all MM-C initially increased but decreased from 2006-2010 except D that showed continued increase (Fig 1A). For race, MM-C were significantly different, with AA having the most C, R, An and D while W having the most B (Fig 1B). Inferior OS was seen with male gender (p=0.006), increasing age, earlier years of diagnosis, belonging to W or H race, C, R and B (all p<0.001), but not with An (p=0.298) or D (p=0.378). Trends in OS over time showed a significant interaction with race in 1991-1995 (p<0.001), 1996-2000 (p=0.004) and 2001-2005 (p<0.001) but not in 2006-2010 (p=0.182), possibly due to shorter follow up. Medicare claims analysis showed that pts receiving any treatment increased from 12.8% in 1991-1995 to 59.3% in 2006-2010 (p<0.001). Specific therapy utilization, including SCT and all drug classes/agents evaluated increased except for cytotoxic chemotherapy utilization (melphalan/cyclophosphamide), which decreased (Fig 2A). Any therapy utilization was significantly different by race (p<0.001) with highest for H (36.5%) and lowest for AA (31.6%). Specific treatments differed significantly by race (Fig 2B). Cost of care analysis showed significant increase over years for median drug claims (0.23k to 3.63k) and total claims (5.11k to 27.8k) during first 6 mth as well as for any time after MM diagnosis (drug: 1.3k to 9.9k, total: 21.9k to 84k) (p<0.001 for all). Median drug claims in first 6 mth were highest among AA (1.3k) and lowest among A (0.63k) (p<0.001). Same was true for total claims in first 6 mth (p<0.001). For any time after diagnosis, H had the highest drug (p<0.001) and total (p=0.081) claims. There were significant interactions between year of diagnosis, race and cost of care with H seeing the highest increase in drug claims in first 6 mth (p<0.001) and any time (p=0.002). Conclusion: MM-C have generally decreased AF-D due to improved therapeutics although AA continue to have the highest rates of MM-C. Our data shows that utilization and cost of MM care have increased tremendously with resulting improved outcomes, but significant racial disparities persist. These disparities may be in part due to impaired access to new agents from lack of supplemental insurance for certain racial groups. Drug utilization and cost of care disparities may also be due to differences in co-morbidities, MM-C or access leading to differential healthcare utilization and should be explored in order to ameliorate disparities in outcomes. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Abstract Background: Outcomes in multiple myeloma (MM) have improved significantly over the years but disparities in outcomes exist among MM patients (pts) belonging to different racial subgroups. Previous studies have explored healthcare access and utilization disparities for pts of different races as potential causes, but genomic differences, which could alter disease biology and clinical behavior, have not been studied. We utilized the MMRF CoMMpass database, which prospectively captures clinical and molecular characteristics of MM patients to explore race-based differences at the genomic level. Methods: The publically available CoMMpass trial database (data release version IA8) was utilized. Pts with race category of White (total n=698) and non-White (total n=223, comprising 129 Blacks, 19 Asians and 45 others) were analyzed for genomics including cytogenetics (fluorescent in situ hybridization; FISH), tumor diploidy (conventional karyotyping), gene expression profiling (GEP), gene copy number variations (CNV), gene single nucleotide variations (SNV) and genomic translocations analysis focused on genes from the FoundationOne Heme panel¨ (402 genes). GEP was considered significantly different between categories for more than or equal to a 2-fold change for a given gene (p<0.05). Categorical variables for FISH probes and diploidy status were compared by Chi-square or Fischer exact test, wherever applicable. Results: GEP clustering analysis uncovered 67 genes differentially expressed between Whites vs. non-Whites (Fig 1A). Baseline cytogenetics aberrations between both race cohorts showed statistically insignificant differences. Multiple cytogenetic abnormalities were seen most commonly in both race groups (~31%) with the distribution of others (in descending order) as such: Del13 > No abnormalities > t(11;14) > 1q amplification > Del17p or p53 > t(4;14) > Del1p > t(14;16) > t(14;20). Aneuploidy status showed insignificant differences between race groups with ~34% of patients from both groups having no aneuploidy. SNV data was present for 90% of Whites and 57% of non-Whites. Overall, 84% of genes had>1 SNV (84%), 2% translocations only and 14% had neither SNVs or translocations. SNVs were classified as Non-specific Non-Synonymous coding (NNSCs), Splice-site (SS) or Tier 1 (T1, codon deletion, insertion, frame-shift, etc.). A total of 880 NNSCs SNVs were observed: 670 in Whites across 227 genes, 210 in non-Whites across 120 genes. In whites, 57% of NNSC SNVs consisted of transition-type mutations and 43% as transversions. In non-Whites, transition mutations comprised 64% of all NNSC SNVs and transversions in the remaining 36%. A total of 38 SS SNVs were observed, 30 in Whites and 8 in non-Whites observed in 25 and 6 genes, respectively. In Whites, 57% of SS SNVs were transition type and remaining 43% were transversion. In non-Whites, an equal % of SS transition and transversion mutations were noted. A total of 240 T1 SNVs were noted; 182 in Whites seen in 82 genes; 58 in non-Whites seen 6 genes. In both Whites and non-Whites, frameshifts (41% in Whites, 47% in non-Whites) and stop-gained (46% in Whites, 45% in non-Whites) SNVs were most common. A total of 17 genes with>10 distinct SNVs were identified in Whites; 5 genes in non-Whites and 4 genes commonly seen in both cohorts (Fig 1B). In Whites, 17 genes were found to have translocations (intrachromosomal TRAF3 and PIK3R2 most common); in non-Whites, 5 genes had translocations (intrachromosomal CIC and EMSY most common). CNV analysis demonstrated 21 genes that were significantly altered with either copy number gain or loss between Whites vs. non-Whites (Fig 1C). Conclusions: We present the first race-based comprehensive genomic analysis utilizing the public interface of the CoMMpass trial. We discovered genomic differences between Whites and non-Whites at several levels including GEP, SNV and CNV, but not at the level of cytogenetics, which are in fact the most commonly performed clinical genomic analysis. Correlation of these variations with MM pt outcomes would be invaluable in understanding disease biology and hopefully mitigating some of the outcome disparities by pt race. As the database grows and becomes more enriched, separate analyses for Blacks, Asians and Hispanics would be attempted. Acknowledgments: We would like to thank the MMRF, Ms. Mary Derome and Dr. Jonathan Keats for providing scientific overview and technical support. Disclosures Fonseca: Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy; BMS: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Bayer: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Novartis: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Sanofi: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms. Ailawadhi:Takeda Oncology: Consultancy; Amgen Inc: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy.

Abstract Background: We have previously reported on ethnic disparities in outcomes of multiple myeloma (MM) pts (pts) and shown that Hispanics have the shortest median overall survival (OS) and myeloma-specific survival (MMS) while Asians have the longest. Ethnic minorities are increasing in number in the United States (US) and have been historically underrepresented in population databases with limited follow up since the introduction of novel agents for MM. We did an updated analysis with longer follow up for ethnic minorities to explore the changes in outcomes by race and also explored MM incidence rates, not reported previously. Methods: Surveillance Epidemiology and End Results (SEER) 13 Registry data (1973-2013) for adult pts (>18 yr) with confirmed diagnosis of MM was utilized. To avoid bias of under representation of ethnic minorities, analysis was restricted to pts diagnosed in 1992 or later. Years of diagnosis were 1992-1995 (pre-stem cell transplant; SCT), 1996-2002 (after SCT but before novel therapeutics) and 2003-2013 (after introduction of novel therapeutics). Cases that received a diagnosis at death certificate/autopsy, without follow-up records, lacking documentation on age at diagnosis, sex, or race/ethnicity were excluded. Cox proportional hazards models were used to evaluate association between patient characteristics and survival. All statistical tests utilized the SAS software (v9.4) and were two-sided with a significance level of 0.05. Results: The final analysis included 68431 MM pts (37300 males; 55%, 31131 females; 45%). Age-group cohorts included: 18-44 yr (2519; 4%), 45-54 yr (8131; 12%), 55-64 yr (15416; 23%), 65-74 yr (20214; 30%), and ≥75 yr (22151; 32%). Mutually exclusive racial subgroups included: non-Hispanic White (NHW; 44618, 65%), non-Hispanic African-American (AA; 13164, 19%), non-Hispanic Asian/Pacific Islanders (API; 3570, 5%), Hispanic (H; 6759, 10%) and Native American (NA; 320, 0.5%). Trends in age-specific incidence rates were similar for all races but except the 20-24 yr group, were highest for AA and lowest for API. (Figure 1) Survival analysis showed that females had a better median OS (3.4 vs 3 yr; p<0.001) and MMS (4.7 vs 4.4 yr; p<0.001) than males. Age was an independent predictor of OS (p<0.001) with the median OS changing from 7.3 yr in 18-44 to 1.9 yr in ≥75 age group. Similar results were seen for age groups and MMS as well (p<0.001). During the three pre-specified time periods for year of diagnosis, both the median OS and MMS progressively improved (P<0.001) suggesting improved outcomes secondary to treatment advancements. H and AA had the worst median OS (3.1 yr) as compared to NHW and API (3.3 yr) (p<0.001) and H had the worst median MMS (4.3 yr) while API had the best (5.1 yr) (p<0.001). Survival analyses were performed for ≥75 age group separately since it was the largest and traditionally with worst outcomes. The difference in median OS by gender was still significant (p<0.001) but less pronounced (1.8 vs 1.9 yr) and was not significant for MMS (p=0.33). Due to less SCT utilization, no incremental OS or MMS benefit was seen prior to advent of novel agents but since 2003 the ≥75 group did have a small benefit for OS (2 vs 1.6 yr, p<0.001) and MMS (3 vs 2.3 yr, p<0.001). Race no longer predicted for a statistically significant OS difference (p=0.52) while for MMS, H continued to have the worst (2.5 yr) and NA the best (3.8 yr) outcome (p<0.001). 5-year relative survival rates (RSR) over time showed an incremental improvement in recent years for all racial groups except API ≥70 yr (Figure 2) with generally an increased incremental benefit for the <70 yr age group than the elderly. For majority of races no incremental benefit was seen in 5-yr RSR for ≥70 yr pts between 1992-1995 and 1996-2003 but improvement was seen in 2004-2013. Conclusions: In a fast changing US demographic mix, significant disparities for MM incidence and outcomes exist by race/ethnicity. As compared to our previous analyses, new trends have emerged with Whites having an improved median OS than AA while H continue to have the worst MMS and API the best. Differences in median OS among races are no longer significant in elderly pts. A modest benefit in OS is being seen for elderly pts since the advent of novel therapeutics. Studies of ethnic disparities are important for evaluating management needs of specific patient populations as well as optimal triaging of healthcare resources. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Kelly: Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Speakers Bureau. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.