Inferior Patient Outcomes Research Articles

MicroRNA-874 suppresses tumor proliferation and metastasis in hepatocellular carcinoma by targeting the DOR/EGFR/ERK pathway

The δ opioid receptor (DOR) is involved in the regulation of malignant transformation and tumor progression of hepatocellular carcinoma (HCC). However, regulation of the DOR in HCC remains poorly defined. We found that miR-874 was identified as a negative regulator of the DOR, which is a direct and functional target of miR-874 via its 3′ untranslated region (UTR). Moreover, miR-874 was downregulated in HCC and its expression was inversely correlated with DOR expression. Downregulation of miR-874 was also associated with larger tumor size, more vascular invasion, a poor TNM stage, poor tumor differentiation, and inferior patient outcomes. Functionally, overexpression of miR-874 in the HCC cell line SK-hep-1 inhibited cell growth, migration, in vitro invasion, and in vivo tumorigenicity. Furthermore, miR-874 overexpression suppressed the DOR, resulting in a downregulated epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) phosphorylation. The EGFR activator—epidermal growth factor (EGF)—can rescue the proliferation and migration suppression induced by miR-874 overexpression, and the rescue effects of the EGF were blocked by an ERK inhibitor. Our study results suggest that miRNA-874 is a negative regulator of the DOR that can suppress tumor proliferation and metastasis in HCC by targeting the DOR/EGFR/ERK pathway, which may be a potential target for HCC treatment.

Inferior long-term allograft and patient outcomes among recipients of offspring living donor kidneys.

While offspring-to-parent living donor kidney transplantations may represent an ideal donor-recipient combination to optimize long-term transplantation outcomes, the sex-specific long-term success of these transplantations remains unclear. We hypothesize that allograft and recipient survivals in offspring-to-parent living donor kidney transplantation differ between men and women due to donor-specific alloimmunization during pregnancy. We retrospectively analyzed long-term allograft and patient survival among men and women who received an offspring living donor kidney compared with those who received other haplotype-matched living donor kidneys. Based on multivariable Cox proportional hazards modeling of Organ Procurement and Transplantation Network data from 2001 to 2015, we found that both men and women who received offspring living donor kidneys had significantly increased mortality compared with recipients who received nonoffspring living donor kidneys. While male recipients of any living donor kidney had greater risk of mortality and allograft failure than female recipients, there was no significant difference in all-cause allograft failure or mortality in male versus female recipients of offspring living donor kidney transplantations. Our analysis demonstrated no significant interaction between recipient sex and donor offspring status. We conclude that nonoffspring living donors should be considered whenever feasible for both men and women with multiple donor options.

Simultaneous Pancreas and Kidney Transplantation is Associated With Inferior Long-Term Outcomes in African Americans

Simultaneous pancreas and kidney transplant (SPK) is the most effective treatment for patients with type 1 diabetes mellitus and renal failure. However, the effect of ethnicity on SPK outcomes is not well understood. We studied the influence of recipient ethnicity on SPK using the United Network for Organ Sharing database. A retrospective review of 20,196 SPK patients from 1989 to 2014 was performed. The recipients were divided into 4 groups: 15,833 whites (78.40%), 2708 African Americans (AA) (14.39%), 1456 Hispanics (7.21%), and 199 Asians (0.99%). Hispanics and Asians experienced the best overall graft and patient outcomes. Both groups demonstrated significantly superior graft and patient survival rates compared with whites at 1, 3, 5, 10, and 15 years (all P < 0.0001). African Americans experienced significantly superior 1- and 3-year patient survival compared with whites (both P < 0.0001). African Americans also experienced significantly superior 1-year kidney and pancreas graft survival compared with whites (P < 0.0001). However, AA experienced significantly inferior patient and allograft outcomes for all other time points compared with whites. Based on United Network for Organ Sharing data from 1989 to 2014, AA have worse long-term patient and graft survival rates compared with whites, Hispanics, and Asians undergoing SPK.

Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia.

Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ⩾1 mutation during remission at a variant allele frequency of ⩾2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (P<0.0001) and, in multivariate analyses adjusting for age, genetic risk, and allogeneic transplantation, with inferior relapse-free survival (hazard ratio, 2.34; P=0039) and overall survival (hazard ratio, 2.14; P=036). Patients with persisting mutations had a higher cumulative incidence of relapse before, but not after allogeneic stem cell transplantation. Our work underlines the relevance of mutation persistence during first remission as a novel risk factor in AML. Persistence of pre-leukemic clones may contribute to the inferior outcome of elderly AML patients. Allogeneic transplantation abrogated the increased relapse risk associated with persisting pre-leukemic clones, suggesting that mutation persistence may guide postremission treatment.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.350.

Impact of BCR-ABL Transcript Subtypes in Achieving Major Molecular Remission in Chronic Phase, Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors

Abstract Introduction: The most common BCR-ABL transcripts are e13a2 (b2a2) and e14a2 (b3a2) reflecting different breakpoints in the BCR gene on chromosome 22. Clinically, their prognostic significance is unclear. Conflicting data exists regarding inferior outcomes in patients expressing e13a2 transcripts. Therefore, we conducted a retrospective study to determine the impact of these transcripts in chronic phase CML patients. Materials and Methods: All consecutive patients with chronic phase CML treated with tyrosine kinase inhibitors at Abington Memorial Hospital were reviewed. Patients expressing e1a2 transcript were excluded. A total of 43 patients were enrolled. Data on demographics, baseline disease characteristics, BCR-ABL subtype, response to TKI as measured by reverse transcription-polymerase chain reaction and outcomes were recorded. Besides descriptive statistics, χ2 and Kaplan-Meier tests were used for data analysis. Results: There were 14 (39.5%) males and 26 (60.5%) females in this study (n = 43). Median age at diagnosis was 60 years (range, 20-87). At diagnosis, median WBC and platelet counts were 50.6 x 103 per µL (range, 2-505) and 269 x 103 per µL (range, 48-1740), respectively. Sokal score was low in 12 (30%), intermediate in 21 (49%) and high in 8 (19%) patients. Thirty-four (72%) patients expressed e13a2, 6 (13%) expressed e14a2 and 7 (15%) co-expressed both. Different TKI modalities included imatinib (n = 11, 23%), dasatinib (n = 18, 38%) nilotinib (n = 14, 30%), bosutinib (n = 2, 4%) and ponatinib (n = 2, 4%). The proportion of patients expressing e13a2, e14a2 and both achieving major molecular remission respectively at 3 months was 26.4%, 0% and 0%, 6 months was 52.9%, 50% and 14.3%, and 12 months was 58.8%, 67% and 28.5%. The proportion of patients expressing e13a2, e14a2 or both who achieved major molecular remission at 12 months was 18 (53%), 4 (67%) and 3 (43%), respectively. Estimated overall survival was not different between cohorts expressing e13a2, e14a2 and both (p value = 0.413). Conclusion: In this study, we did not find any difference in outcomes in patients with CML expressing e13a2, e14a2 or both. Even though patients expressing e13a2 achieved faster remissions, overall survival was the same in all cohorts. Future studies are needed to further evaluate the prognostic impact of various BCR-ABL transcripts in CML patients. Disclosures No relevant conflicts of interest to declare.

The Association Between Sarcopenia and Oncologic Outcomes After Radical Prostatectomy.

Sarcopenia is associated with inferior perioperative and oncologic outcomes in patients undergoing surgery for multiple malignancies. The purpose of this study was to evaluate the association between sarcopenia and outcomes after radical prostatectomy (RP) for men with prostate cancer. Using a representative computed tomographic image from the L3 level, preoperative skeletal muscle indices (SMI) calculated for 698 patients who underwent RP between 2007 and 2010. Patients were classified as sarcopenic if they had a SMI<55cm2/kg2 according to international consensus. The associations between sarcopenia and biochemical recurrence (BCR), systemic progression (SP), and all-cause mortality (ACM) were investigated by Cox proportional hazards regression. Sarcopenic patients were older than nonsarcopenic patients (mean age, 63.0 vs. 60.4 years, P< .001) but were otherwise similar with regard to clinical and pathologic characteristics. There was no significant difference in the perioperative complication rate after RP between sarcopenic and nonsarcopenic patients (16.5% vs. 17.4%, P= .82). At a median follow-up after surgery of 6.0 years, 152 patients were diagnosed with BCR, patients were diagnosed with SP, and 50 patients died. In multivariable analysis, the presence of sarcopenia was not significantly associated with the risks of BCR, SP, or ACM. Similar results were obtained when analyzing SMI as a continuous variable. Sarcopenia was not found to be independently associated with perioperative complications or oncologic outcomes after RP. As such, the presence of sarcopenia may not be prognostic marker for inferior outcomes among men with localized prostate cancer undergoing RP.

Obesity negatively impacts outcome in elderly female patients with aggressive B-cell lymphomas treated with R-CHOP: results from prospective trials of the German high grade non-Hodgkin's lymphoma trial group.

To study if obesity is a risk factor in elderly patients (>60years) with aggressive B-cell lymphoma, the outcomes of 576 elderly patients treated with rituximab in the RICOVER-60 trial were analysed in a retrospective study with regard to body mass index (BMI) and gender. Of the 576 patients, 1% had low body weight (BMI<18·5), 38% were normal weight (18·5≤BMI<25), 42% were overweight (25≤BMI<30) and 19% were obese (BMI≥30). Event-free (EFS), progression-free (PFS) and overall survival (OS) according to BMI showed no significant differences for all and for male patients. EFS (P=0·041), PFS (P=0·038) and OS (P=0·031) were significantly better for female non-obese patients. A multivariate analysis adjusted for International Prognostic Index risk factors confirmed these results, with the following hazard ratios (HR) for obesity (BMI≥30) for EFS/PFS/OS: all patients - 1·4/1·4/1·4 (not significant); male patients - 1·2/1·2/1·0 (not significant) and female patients - 1·7 (P=0·032)/1·9 (P=0·022)/2·0 (P=0·017). In conclusion, obesity is a risk factor that influences treatment outcome in elderly female patients with aggressive B-cell lymphoma treated with R-CHOP (rituximab+cyclophosphamide, doxorubicin, vincristine, prednisolone). The inferior outcomes in obese female patients may be due to faster rituximab clearance in obese females.

Alteration of mitochondrial biogenesis promotes disease progression in multiple myeloma.

Many cancers, including multiple myeloma (MM), retain more cytosolic iron to promote tumor cell growth and drug resistance. Higher cytosolic iron promotes oxidative damage due to its interaction with reactive oxygen species generated by mitochondria. The variation of mitochondrial biogenesis in different stages of MM disease was evaluated using gene expression profiles in a large clinical dataset. Sixteen of 18mitochondrial biogenesis related gene sets, including mitochondrial biogenesis signature and oxidative phosphorylation, were increased in myeloma cells compared with normal plasma cells and high expression was associated with an inferior patient outcome. Relapsed and drug resistant myeloma samples had higher expression of mitochondrial biogenesis signatures than newly diagnosed patient samples. The expression of mitochondrial biogenesis genes was regulated by the cellular iron content, which showed a synergistic effect in patient outcome in MM. Pharmacological ascorbic acid induced myeloma cell death by inhibition of mitochondria oxidative phosphorylation in an in vivo model. Here, we identify that dysregulated mitochondrial biogenesis and iron homeostasis play a major role in myeloma progression and patient outcome and that pharmacological ascorbic acid, through cellular iron content and mitochondrial oxidative species, should be considered as a novel treatment in myeloma including drug-resistant and relapsed patients.

Pre-treatment lymphopenia and indication of tumor-induced systemic immunosuppression in medulloblastoma.

The presence of tumor-induced systemic immune suppression, including lymphopenia, has been recognized in adult patients with glioblastoma for several decades, and pre-treatment neutrophil-to-lymphocyte count ratio (NLCR) is associated with inferior clinical outcome in patients with glioblastoma. Whether tumor-induced systemic immune suppression is also present in children with malignant brain tumors is not known. We performed a retrospective analysis of pretreatment neutrophil and lymphocyte counts in pediatric patients with medulloblastoma (MB) compared to a control group of children with posterior fossa pilocytic astrocytoma (PA). Compared to the control group, we observed statistically significantly lower absolute lymphocyte counts (ALCs) and higher NLCRs in the medulloblastoma group. Our findings suggest the presence of tumor-induced systemic immune suppression in MB patients already present at the time of diagnosis, with potential implications for the development of immune therapies in this population.

The Impact of Chronic Kidney Disease on Postoperative Outcomes in Patients Undergoing Lumbar Decompression and Fusion.

To determine whether preoperative chronic kidney disease (CKD) is associated with inferior perioperative outcomes in patients undergoing lumbar arthrodesis. Medical records of 293 adult (≥18 years old) patients with spine deformity undergoing elective lumbar spine decompression and fusion at a major academic institution from 2006 to 2015 were reviewed. We identified 18 (6.1%) patients with a clinical diagnosis of CKD (CKDgroup, n= 18; no-CKD group, n= 275). Patient demographics, comorbidities, and intraoperative and postoperative complication rates were collected for each patient. The primary endpoint was incidence of postoperative complications. Patient demographics, including age, sex, and body mass index, and comorbidities were similar between cohorts. The CKD group had a significantly higher prevalence of hypertension, hyperlipidemia, and anemia compared with the no-CKD group. Median number of fusion levels, length of surgery, and estimated blood loss were similar between both cohorts. Postoperative complication profile was significantly different between the cohorts, with the CKD group having a significantly higher proportion of patients transferred to the intensive care unit (52.9% vs. 29.3%, P= 0.04) with episodes of delirium (27.8% vs. 8.4%, P= 0.007), urinary tract infection (27.8% vs. 6.9%, P=0.0002), and deep vein thrombosis (5.6% vs. 0.4%, P= 0.01). Although not significant, the CKD group had a 2-fold higher rate of 30-day readmissions compared with the no-CKD group (CKD group: 27.8% vs. no-CKD group: 12.7%, P= 0.07). Our study suggests that patients with CKD may be more likely to develop perioperative complications after lumbar arthrodesis. Future studies are necessary to corroborate our findings.

The international staging system improves the IPI risk stratification in patients with diffuse large B-cell lymphoma treated with R-CHOP

The international staging system (ISS), based on serum beta-2 microglobulin and albumin, is used to predict survival in multiple myeloma, but its prognostic significance in diffuse large B-cell lymphoma (DLBCL) remains unknown. Herein, we retrospectively analyzed 215 de novo DLBCL patients. According to ISS, there were 90 of 215 (41.9%) patients in stage I, 98 of 215 (45.6%) in stage II and 27 of 215 (12.6%) in stage III group. Patients with ISS stage II/III showed shorter overall survival (OS) and event free survival (EFS) than those with stage I treated with R-CHOP (p = 0.012 and p = 0.043, respectively), but not those treated with CHOP regimen (p > 0.05). Multivariable analysis revealed that ISS, independent of IPI, indicated different survival in both OS (HR, 5.690; 95% CI, 1.270–25.495, p = 0.023) and EFS (HR, 2.116; 95% CI, 1.005–4.455, p = 0.049) in DLBCL patients treated with R-CHOP. ISS could identify patients with better outcome in intermediate-high/high IPI risk patients (p < 0.05). Our data suggests that advanced ISS stage is associated with inferior outcome in DLBCL patients treated with R-CHOP. ISS could identify a subgroup of DLBCL patients with superior outcome from high IPI risk patients, which may help to avoid intensive therapy.

Crizotinib, a MET inhibitor, inhibits growth, migration, and invasion of breast cancer cells in vitro and synergizes with chemotherapeutic agents.

MET is a receptor tyrosine kinase known for its pleiotropic effects in tumorigenesis. Dysregulations of MET expression and/or signaling have been reported and determined to be associated with inferior outcomes in breast cancer patients rendering MET a versatile candidate for targeted therapeutic intervention. Crizotinib is a multi-targeted small-molecule kinase inhibitor for MET, ALK, and ROS1 kinases. This study evaluated the anti-proliferative, cytotoxic, anti-migratory, and anti-invasive effects of crizotinib in breast cancer cells in vitro. Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) colorimetric assay. In vitro wound-healing assay was used to examine the effect of crizotinib on breast cancer cell migration. The expressions of Ki-67, MET, and phospho-MET receptors were characterized using immunofluorescence staining. Results showed that crizotinib has significant anti-proliferative activity on all mammary tumor cells with IC50 values of 5.16, 1.5, and 3.85 µM in MDA-MB-231, MCF-7, and SK-BR-3 cells, respectively. Crizotinib induced cytotoxic effects in all breast cancer cells examined. Combined treatment of small dose of crizotinib with paclitaxel or doxorubicin exhibited a highly synergistic inhibition of growth of MDA-MB-231 and MCF-7 cells with combination index values <1 while no significant effect was observed in SK-BR-3 cells compared with individual compounds. Treatment with crizotinib demonstrated a remarkable reduction in the expression of Ki-67 protein in all 3 tested cell lines. Crizotinib inhibited migration and invasion of MDA-MB-231 cells in a dose-dependent fashion. Crizotinib reduced MET receptor activation in MDA-MB-231 cells when treated at effective concentrations. In conclusion, crizotinib suppressed proliferation, migration, and invasion of breast cancer cells in vitro. The results of this study demonstrated that combined treatment of crizotinib with chemotherapeutic agents resulted in a synergistic growth inhibition of specific breast cancer cell lines.

Impact of Protease Inhibitor-Based Anti-Retroviral Therapy on Outcomes for HIV+ Kidney Transplant Recipients.

Excellent outcomes have been demonstrated among select HIV-positive kidney transplant (KT) recipients with well-controlled infection, but to date, no national study has explored outcomes among HIV+ KT recipients by antiretroviral therapy (ART) regimen. Intercontinental Marketing Services (IMS) pharmacy fills (1/1/01-10/1/12) were linked with Scientific Registry of Transplant Recipients (SRTR) data. A total of 332 recipients with pre- and posttransplantation fills were characterized by ART at the time of transplantation as protease inhibitor (PI) or non-PI-based ART (88 PI vs. 244 non-PI). Cox proportional hazards models were adjusted for recipient and donor characteristics. Comparing recipients by ART regimen, there were no significant differences in age, race, or HCV status. Recipients on PI-based regimens were significantly more likely to have an Estimated Post Transplant Survival (EPTS) score of >20% (70.9% vs. 56.3%, p=0.02) than those on non-PI regimens. On adjusted analyses, PI-based regimens were associated with a 1.8-fold increased risk of allograft loss (adjusted hazard ratio [aHR] 1.84, 95% confidence interval [CI] 1.22-2.77, p=0.003), with the greatest risk observed in the first posttransplantation year (aHR 4.48, 95% CI 1.75-11.48, p=0.002), and a 1.9-fold increased risk of death as compared to non-PI regimens (aHR 1.91, 95% CI 1.02-3.59, p=0.05). These results suggest that whenever possible, recipients should be converted to a non-PI regimen prior to kidney transplantation.

Kidney dysfunction after cardiac transplantation: does early acute kidney injury translate into inferiorlong-term patient and renal outcomes? - aretrospective cohort study.

Kidney dysfunction after cardiac transplantation: does early acute kidney injury translate into inferiorlong-term patient and renal outcomes? - aretrospective cohort study.

Do Ligamentum Teres Tears Portend Inferior Outcomes in Patients With Borderline Dysplasia Undergoing Hip Arthroscopic Surgery? A Match-Controlled Study With a Minimum 2-Year Follow-up

Background: Arthroscopic surgery in borderline dysplastic hips remains controversial, but the role of the ligamentum teres (LT) has not been studied in this setting. Hypothesis: Borderline dysplastic patients with LT tears have worse short-term outcomes than those without LT tears. Study Design: Cohort study; Level of evidence, 3. Methods: Data were prospectively collected on patients who underwent arthroscopic surgery between February 2008 and April 2014. The inclusion criteria were borderline dysplasia (lateral center-edge angle [LCEA], 18°-25°) and labral tears; arthroscopic treatments including labral preservation and capsular plication; and preoperative patient-reported outcome scores including the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score–Sport-Specific Subscale, and visual analog scale for pain. Patients were excluded for preoperative Tönnis osteoarthritis grade >0, workers’ compensation claims, previous ipsilateral hip surgery and conditions, or frank dysplasia (LCEA <18°). Patients with LT tears were pair-matched to patients without tears for sex, age at surgery ±10 years, body mass index (<30 kg/m2 vs ≥30 kg/m2), labral treatment type, and microfracture. Results: Of 68 eligible patients, 63 (93%) had a minimum 2-year follow-up, and 30 (48%) had LT tears. Twenty patients in each group were pair-matched. The mean follow-up time was 54.3 months (range, 24.2-83.8 months) for the LT tear group and 38.6 months (range, 24.6-70.6 months) for the control group (P = .002). Ninety percent were female. There were no significant differences regarding demographics or intra-operative procedures. The LT tear group trended toward lower postoperative mHHS (P = .09) and NAHS (P = .09) values. Mean satisfaction was 8.1 for the LT tear group and 7.9 for the control group. Preoperative and follow-up scores were not significantly different between the groups. The LT tear group had 5 revisions, with 1 revision in the control group. Three patients (15%) in the LT tear group underwent total hip arthroplasty (THA); no patients in the control group required THA. Conclusion: In borderline dysplastic patients undergoing hip arthroscopic surgery with labral treatment and capsular plication, LT tears may indicate advanced instability and portend slightly inferior outcomes when compared with a match-controlled group. Borderline dysplastic patients with LT tears may have increased propensities toward revision arthroscopic surgery and conversion to THA. LT tears in these patients may warrant consideration for additional procedures including periacetabular osteotomy and LT reconstruction.

CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers.

The prognostic value of CpG island methylator phenotype (CIMP) in colorectal cancer remains unsettled. We aimed to assess the prognostic value of this phenotype analyzing a total of 1126 tumor samples obtained from two Norwegian consecutive colorectal cancer series. CIMP status was determined by analyzing the 5‐markers CAGNA1G, IGF2, NEUROG1, RUNX3 and SOCS1 by quantitative methylation specific PCR (qMSP). The effect of CIMP on time to recurrence (TTR) and overall survival (OS) were determined by uni‐ and multivariate analyses. Subgroup analyses were conducted according to MSI and BRAF mutation status, disease stage, and also age at time of diagnosis (<60, 60‐74, ≥75 years). Patients with CIMP positive tumors demonstrated significantly shorter TTR and worse OS compared to those with CIMP negative tumors (multivariate hazard ratio [95% CI] 1.86 [1.31‐2.63] and 1.89 [1.34‐2.65], respectively). In stratified analyses, CIMP tumors showed significantly worse outcome among patients with microsatellite stable (MSS, P < 0.001), and MSS BRAF mutated tumors (P < 0.001), a finding that persisted in patients with stage II, III or IV disease, and that remained significant in multivariate analysis (P < 0.01). Consistent results were found for all three age groups. To conclude, CIMP is significantly associated with inferior outcome for colorectal cancer patients, and can stratify the poor prognostic patients with MSS BRAF mutated tumors.

Additional–structural–chromosomal aberrations are associated with inferior clinical outcome in patients with hyperdiploid multiple myeloma: a single-institution experience

Multiple myeloma is cytogenetically heterogeneous and a hyperdiploid karyotype is considered currently to have standard risk. In this study, we investigated the clinical impact of additional–structural–chromosomal aberrations assessed by chromosome analysis in 284 patients with a hyperdiploid karyotype that were subdivided into four groups based on the complexity of additional–structural–chromosomal aberrations: group 1, no additional–structural–chromosomal aberrations (n=35); group 2, one additional–structural–chromosomal aberration (n=46); group 3, two additional–structural–chromosomal aberrations (n=39); group 4, ≥three additional–structural–chromosomal aberrations (n=164). Clinicopathological data among these groups showed no differences, except patients in group 1 had higher hemoglobin (P=0.031) and albumin (P=0.045) levels. The median follow-up was 55 months (range, 3–221). The median overall survival of patients in groups 1–4 was negatively correlated with the number of the additional–structural–chromosomal aberrations: 98, 76, 61, and 48 months, respectively (P<0.0001). In group 4, CKS1B gain, RB1, or TP53 deletions had no additional impact on overall survival; however, trisomy 3 or 15 conferred a much better overall survival, and monosomy 13 and 14 predicted a worse outcome. In addition, the overall survival of patients in groups 3 and 4 was similar to a subset of high-risk multiple myeloma cases (n=21) (P=0.387). About 192 (67.6%) patients who received stem cell transplantation did not show improved overall survival compared with non-stem cell transplantation patients (n=92; P=0.142) overall; however, they did show significantly improved overall survival in patients with refractory disease in group 4 (P=0.0084). Multivariate analysis showed that two or more additional–structural–chromosomal aberrations (P<0.0001), stages (P=0.02 and P=0.002) and relapsed disease (P=0.009) negatively impacted the overall survival. We conclude that hyperdiploid karyotypes in multiple myeloma are associated with additional–structural–chromosomal aberrations and a greater number of additional–structural–chromosomal aberrations predicts poorer clinical outcome. A hyperdiploid karyotype with ≥2 additional–structural–chromosomal aberrations at chromosomal level should be considered an independent high-risk factor.

The prognostic role of preoperative serum lactate dehydrogenase (LDH) in patients with resected advanced melanoma.

e21054 Background: Up to 50% of patients undergoing resection for advanced melanoma experience recurrence. Identification of preoperative prognostic biomarkers is needed to ascertain risk of relapse and guide postoperative management. Lactate dehydrogenase (LDH) represents a strong prognostic factor in unresectable metastatic (stage IV) melanoma, but its relevance in patients with resected stage III or IV disease remains unknown. Methods: We retrospectively analyzed data from patients with stage III and IV melanoma who had undergone complete resection of disease and received follow-up treatment at Mayo Clinic, Rochester between January 1, 2000 and January 31, 2012. Clinical data were collected from electronic records. Survival data were estimated using the Kaplan-Meier method. Associations of preoperative LDH with time to relapse and death were evaluated using Cox proportional hazards regression models and summarized with hazard ratios and 95% confidence intervals. Results: A total of 154 subjects with resectable stage III or IV melanoma were included in the study. Median age at the time of resection was 58; 54 (35.1%) were female. One-hundred sixteen (75.3%) patients were classified as stage III and 38 (24.7%) stage IV. Adjuvant systemic treatment was administered in 75 (48.7%) patients and adjuvant radiation in 32 (20.7%). Median duration of follow-up was 4.0 years. Sixteen (10.3%) patients had preoperative LDH above the upper limit of normal. Each 50-unit increase in LDH was associated with a 15% increased risk of relapse (HR 1.15; p = 0.040) and 23% increased risk of death (HR 1.23; p = 0.001). After adjusting for age, gender, stage, number of sites, adjuvant systemic treatment, and adjuvant radiation, preoperative LDH remained associated with time to death (HR 1.25; p = 0.002). Preoperative LDH greater than the upper limit of normal was associated with increased hazard of death, both with univariate (HR 2.44; p = 0.005) and multivariate (HR 2.17; p = 0.017) analyses. Conclusions: This study supports the role of elevated preoperative LDH as a predictor of inferior outcomes in patients with advanced melanoma. Further study to correlate LDH to outcomes in the era of adjuvant immunotherapy is required.

Diabetic kidney transplant recipients: Impaired infection control and increased alloreactivity.

Post-transplantation diabetes mellitus (PTDM) has been associated with inferior patient and allograft outcomes. However, previous studies did not identify differences in infection control and alloreactivity. We studied 449 kidney transplant recipients (KTRs) between 2005 and 2013. Fifty (11.1%) KTRs were diagnosed with PTDM and 60 (13.4%) KTRs with pre-existing diabetes. Samples were collected pretransplantation, at +1, +2, +3months post-transplantation. CMV specific and alloreactive T cells were quantified by interferon-γ Elispot assay. Lymphocyte subpopulations were quantified by flow cytometry. Upon multivariate analysis, age, obesity, and the use of tacrolimus increased the risk of PTDM (P<.05). KTRs with pre-existing diabetes/PTDM showed higher rates of sepsis (P<.01). Total CD3+ and CD4+ T cell counts were significantly lower in KTRs with PTDM/pre-existing diabetes post-transplantation (P<.05). No differences were observed for CMV-specific T cells between any group (P>.05). KTRs developing PTDM showed increased frequencies of alloreactive T-cells post-transplantation (P<.05). Our results suggest higher rates of infection in KTRs with pre-existing diabetes/PTDM that may be attributed to impaired overall immunity. Higher frequencies of alloreactive T cells contribute to inferior long-term outcomes. As acute rejection, but not pre-existing diabetes/PTDM, was associated with inferior allograft survival and function, maintaining adequate immunosuppression to prevent rejection seems important.

The Impact of Quality Variations on Patients Undergoing Surgery for Renal Cell Carcinoma: A National Cancer Database Study

BackgroundDespite efforts to define metrics assessing hospital-level quality for renal cell carcinoma (RCC) surgical care there remains a paucity of real-world data validating their ability to benchmark performance. Consequently, whether poor performance on hospital-level quality indicators is associated with inferior patient outcomes remains unknown. ObjectivesTo determine hospital-level variations in RCC surgical quality after adjusting for differences in patient- and tumor-specific factors. Further, to determine associations between hospital-level quality performance and surgical volume, academic affiliation, and patient mortality. Design, setting, and participantsRCC patients undergoing surgery in the USA and Puerto Rico (2004–2014) were identified from the National Cancer Database. Outcome measures and statistical analysisHospital-level quality of care was assessed according to disease-specific process and outcome quality indicators. Case-mix adjusted hospital benchmarking was performed using indirect standardization methodology and multivariable regression models. A composite measure of quality, the Renal Cancer Quality Score (RC-QS), was subsequently derived and associations between RC-QS and surgical volume, academic affiliation, and patient mortality were determined. Results and limitationsOver 1100 hospitals were benchmarked for quality, with 10–31% identified as providing poor care for a given quality indicator. Lower RC-QS hospitals had smaller referral volumes and were less academic compared with higher RC-QS hospitals (p<0.001). Higher RC-QS was independently associated with lower 30-d, 90-d, and overall mortality (adjusted odds ratio [confidence interval]: 0.92 [0.90–0.95], odds ratio: 0.94 [0.91–0.96], hazard ratio: 0.97 [0.96–0.98] per unit increase, respectively). These data are retrospective and it is unknown whether improvement in the RC-QS improves outcomes. ConclusionsWidespread hospital-level variations in RCC surgical quality exist, as captured by the RC-QS. Superior quality is associated with improved patient outcomes, including mortality benefit. The RC-QS serves as a benchmarking tool for RCC quality that can provide audit level feedback to hospitals and policymakers for quality improvement. Patient summaryWe benchmarked hospital performance across quality indicators for kidney cancer surgical care. Overall, large variations in quality exist, with high volume academic hospitals demonstrating superior performance and improved patient survival. These data can inform hospitals and policymakers for quality improvement initiatives.