Multivariate Analysis HR Research Articles

One-year survival according to use of thrombus aspiration for primary PCI in the real-world. The FAST-MI 2010 registry

Background: Whether the use of thrombus aspiration during primary PCI for STEMI is associated with decreased mortality remains a matter of debate. We assessed one-year survival in STEMI patients participating in the FAST-MI 2010 registry according to use of thrombus aspiration during primary PCI. Methods: FAST-MI 2010 is a nationwide French registry that included 4169 patients with AMI at the end of 2010 in 213 centres (76% of active centres in France). Of those, 2438 had STEMI or LBBB, of whom 1497 had primary PCI, with thrombus aspiration used in 663 (44%). Results: Patients with thrombus aspiration were younger (61 vs 63 yrs, P=0.01), with a similar GRACE score (140 vs 143, P=0.10) and a shorter median time from symptom onset (245 vs 285 min, P=0.001), and they were more often admitted to academic hospitals (46% vs 35%, P<0.001); location of AMI, history of MI, PCI or CABG did not differ significantly. Thirty-day mortality was 2.1% vs 2.3% (P=0.71) and one-year survival was 95.5% vs 94.8%, P=0.59. Using fully adjusted Cox multivariate analysis HR (95% CI) for one-year death was 1.02 (0.54-1.91), P=0.96. A propensity score for getting thrombus aspiration was calculated and two groups of 550 patients each with similar baseline characteristics were compared: 30-day death was 1.1 vs 1.5% (P=0.59), and one-year survival was 96.4 vs 96.2%, P=0.90 (Figure) ![Figure][1] One-year survival in matched cohorts Conclusion: The use of thrombus aspiration in this real-world setting was not associated with improved one-year survival. [1]: pending:yes

The association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer.

6068 Background: Severe treatment-related lymphopenia (TRL) occurs in 50% of glioblastoma and pancreatic cancer patients and is associated with early death from tumor progression. We sought to determine if similar findings were seen in head and neck squamous cell carcinoma (HNSCC). Methods: Eligible patients for this retrospective study had: 1) HNSCC cancer diagnosed in 2007-2009, 2) good performance status, 3) platinum-based chemoradiation, and 4) follow-up at Johns Hopkins. Serial total lymphocyte counts (TLC), overall survival (OS) and progression-free survival (PFS) were analyzed accounting for known prognostic factors. Results: Fifty-six adults met eligibility criteria: median age: 57 years, female: 21%, HPV+: 61%, surgery prior to chemoradiation: 16%, stage IVA-IVB: 77%, T stage 3-4: 40% and N stage 2b-3: 56%. Changes in TLC are shown below (Table). 14/56 patients (25%) had tumor recurrence and 9 (16%) died of their tumor. HPV+ patients had longer PFS (p=0.01) and OS (p=0.006) than HPV- patients. 10/22 HPV- patients had disease progression and 7 died. HPV- patients who developed grade III-IV TRL two months after beginning chemoradiation had a strikingly higher hazard rate for disease progression than those whose TLC remained higher (multivariate analysis HR 6.2, 95%CI: 1.1-35.2; p=0.039). Too few events occurred in the HPV+ cohort for analysis. Conclusions: TLCs were normal before chemoradiation. However, two months after chemoradiation ~60% of patients had severe TLC regardless of HPV status. HPV- patients with severe TRL were much more likely to have disease progression than those without TRL. Prospective studies are needed to confirm these findings which are similar to those reported in other cancers. Preservation of the immune system during chemoradiation may be important to improving PFS and OS. [Table: see text]

Abstract 2420: The association between severe treatment-related lymphopenia and progression free survival in patients with newly diagnosed squamous cell head and neck cancer.

Abstract Background: Severe treatment-related lymphopenia (TRL) occurs in 50% of glioblastoma and pancreatic cancer patients and is associated with early death from tumor progression. We sought to determine if similar findings were seen in head and neck squamous cell carcinoma (HNSCC). Patients and Methods: Eligible patients for this retrospective study had: 1) HNSCC cancer diagnosed in 2007-2009, 2) good performance status, 3) platinum-based chemoradiation, and 4) follow-up at Johns Hopkins. Serial total lymphocyte counts (TLC), overall survival (OS) and progression-free survival (PFS) were analyzed accounting for known prognostic factors. Results: Fifty-six adults met eligibility criteria: median age: 57 years, female: 21%, HPV+: 61%, surgery prior to chemoradiation: 16%, stage IVA-IVB: 77%, T stage 3-4: 40% and N stage 2b-3: 56%. Changes in TLC are shown below: Median TLC:Baseline Median TLC: 2 months post-Rx % with TLC &amp;lt;500: 2 months post-Rx Overall 1660 448 61% HPV- (n = 22) 1770 550 36% HPV+ (n = 34) 1610 320 76% 14/56 patients (25%) had tumor recurrence and 9 (16%) died of their tumor. HPV+ patients had longer PFS (p=0.01) and OS (p=0.006) than HPV- patients. 10/22 HPV- patients had disease progression and 7 died. HPV- patients who developed grade III-IV TRL two months after beginning chemoradiation had a strikingly higher hazard rate for disease progression than those whose TLC remained higher (multivariate analysis HR 6.2, 95%CI: 1.1-35.2; p=0.039). Too few events occurred in the HPV+ cohort for analysis. Conclusion: TLCs were normal before chemoradiation. However, two months after chemoradiation ∼60% of patients had severe TLC regardless of HPV status. HPV- patients with severe TRL were much more likely to have disease progression than those without TRL. Prospective studies are needed to confirm these findings which are similar to those reported in other cancers. Preservation of the immune system during chemoradiation may be important to improving PFS and OS. Citation Format: Jian L. Campian, Guneet Sarai, Xiaobu Ye, Shanthi Marur, Stuart A. Grossman. The association between severe treatment-related lymphopenia and progression free survival in patients with newly diagnosed squamous cell head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2420. doi:10.1158/1538-7445.AM2013-2420 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Lack of Prognostic Significance of Monosomal Karyotype and Absolute Lymphocyte Count At Diagnosis in Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia

AbstractAbstract 1476 Background:Monosomal Karyotype (MK) is defined as the presence of two or more autosomal monosomies or one autosomal monosomy and one structural abnormality. MK has been found to be an independent poor prognostic factor in myeloid diseases (Patnaik et al, Leukemia 2011, Haferlach et al, Blood 2012) even in the setting of allogeneic stem cell transplantation (Fang et al, Blood 2011). The prognostic relevance of MK in Acute Lymphoblastic Leukemia (ALL) is unknown. Absolute lymphocyte count (ALC) at diagnosis, on the other hand, has been shown to be prognostic in a variety of lymphoproliferative disorders (Porrata et al, Leukemia 2010). However, the prognosis of ALC at diagnosis in ALL is undetermined Methods:This is a retrospective analysis of the Mayo Clinic leukemia database (1998–2010). The study was approved by the Institutional Review Board. Outcomes analyzed included overall survival (OS), leukemia free survival (LFS) and relapse rate. Clinical characteristics, cytogenetics, therapy and outcomes of patients with Philadelphia negative ALL (Ph-negative ALL) were analyzed. Cytogenetics were classified as follows: standard risk [hyperdiploidy], intermediate risk [Normal, del(11q)-not MLL, del(6q), del(17p), del(9p), del(12p), del(13q), t(14q32), t(10;14), low hyperdiploidy, others], high risk [-7, del(7p), +8, MLL translocations, t(1;19), t(17;19), t(5;14)], and very high [t(4;11), t(8;14), complex (≥5 abnormalities), hypodiploidy, triploidy] (Pullarkat et, Blood 2008). Multivariate analysis was performed using Cox Regression Model. Results:Between 1998 and 2010, a total of 175 consecutive patients with ALL were identified. Of these, 112 (64%) had Ph-negative ALL. The median age was 39.5 (16–88) years and 74 were male (66%). The majority of cases were B-ALL (78 patients, 69%). At presentation, the median hemoglobin was 10 (4.1–18.5) g/dL, platelet count was 61 (3–523) ×10(9)/L, WBC was 7.2 (0.8–377) ×10(9)/L and ALC was 1.9 (0–69.0) ×10(9)/L. The ALC was > 1000 in 75 (71%) patients. Cytogenetics risk categories were as follows: standard risk in 5 (4.4%), intermediate risk in 70 (62.5%), high risk in 8 (7.1%) and very high risk in 29 (25.9%) patients. Twenty-two patients (20.9%) presented with extranodal disease (CNS disease in 13 patients, 11.6%). Six patients (5.4%) had prior exposure to chemotherapy. Treatment involved allogeneic stem cell transplantation (SCT) in 34 (30.4%) patients. The median OS for the whole cohort was 24 (0–206) months and LFS was 18 (0–193) months. Forty four patients (39.3%) relapsed after achieving initial remission with a median time to relapse of 15 (2–73) monthsIn a univariate analysis, low platelet count at diagnosis, poor ECOG performance status (PS), and high or very high risk cytogenetics risk categories were associated with inferior OS. ALC at diagnosis did not impact OS or LFS. On a multivariate analysis, high/very high risk cytogenetics, low platelet counts and poor ECOG PS were independent predictors of inferior outcomes.Nineteen patients (16.9%) had a MK. Of these, 16 (84.2%) fell in the very high risk cytogenetics category regardless of MK status. Three patients (1.6%) presented with extramedullary disease and six (3.2%) underwent SCT. The median OS of these 19 patients was 15 (1–73) months. While MK was associated with inferior LFS and a trend towards worse OS, this was not significant on a multivariate model that included cytogenetic risk categories, thrombocytopenia and the ECOG PS. Conclusions:Our study demonstrates that cytogenetics risk stratification, thrombocytopenia and ECOG performance status are independent prognostic factors in ALL. MK and ALC at diagnosis had no prognostic significance.Table 1Prognostic Variables Affecting Overall Survival in 112 Patients with Ph-Negative ALLVariableP value (univariate analysis)P value (multivariate analysis)HR (multivariate analysis)Gender0.98Hemoglobin at diagnosis0.53WBC count at diagnosis0.5Platelet count at diagnosis0.020.0450.2-0.8ANC at diagnosis0.18ALC at diagnosis0.1LDH at diagnosis0.1Cytogenetics risk categories0.00090.0060.1-1.0Presence of MK0.06Exposure to chemotherapy0.45Extranodal disease0.2ECOG performance status0.00040.00041.6-4.3*WBC=white blood cell, ANC=absolute neutrophil count, ALC=absolute lymphocyte count, LDH=lactate dehydrogenase, MK=monosomal karyotype, ECOG=Eastern Cooperative Oncology Group. Disclosures:No relevant conflicts of interest to declare.

Intracranial Hemangiopericytoma and the Role of Radiation Therapy

Intracranial hemangiopericytoma (HPC) is a rare malignancy for which treatment recommendations vary. We sought to characterize outcomes of HPC patients treated with postoperative external beam radiotherapy (PORT). A retrospective analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) Program of the US National Cancer Institute. We identified patients with intracranial hemangiopericytoma who underwent surgery alone or PORT. We identified 88 patients with a diagnosis of HPC between 1982 and 2009 treated with surgery alone or PORT. The majority of patients were female (53%) and white (84%) with a median age of 50.5 years (range, 0-92 years). Gross total resection (GTR) was achieved in 55%, and PORT was delivered to 48% of the entire cohort. The median overall survival (OS) and cause-specific survival (CSS) were 111 months and 161 months, respectively. On univariate analysis, age older than 50 years correlated with poor OS (hazard ratio [HR]: 3.43; 95% confidence interval [CI]: 1.70-6.95; P = .001) and CSS (HR: 2.77; 95% CI: 1.18-6.48; P = .019). On multivariate analysis (MVA), age >50 years correlated with poor OS (HR: 3.69; 95% CI: 1.72-7.93; P = .001) and CSS (HR: 2.67; 95% CI: 1.08-6.59; P = .034). On MVA, GTR correlated with improved OS (HR: 0.28; 95% CI: 0.11-0.71; P = .007) and CSS (HR: 0.23; 95% CI: 0.07-0.76; P = .016). In addition, PORT correlated with improved OS (MVA HR: 0.02; 95% CI: 0.00-0.31; P = .005) and CSS (MVA HR: 0.02; 95% CI: 0.00-0.45; P = .015). Patients undergoing STR with PORT compared favorably with those undergoing GTR alone with respect to OS (HR: 0.43; 95% CI: 0.15-1.26; P = .13) and CSS (HR: 0.51; 95% CI: 0.15-1.78; P = .29). In intracranial HPC, both PORT and GTR independently correlate with improved OS and CSS.

Cardiac Autonomic Function and Cardiovascular Response to Exercise in Patients with Chronic Obstructive Pulmonary Disease

Background: Chronic obstructive pulmonary disease (COPD) is associated with impaired exercise tolerance, but it has not been established to what extent cardiac autonomic function impacts on exercise capacity. Objective: To evaluate whether there is an association between airflow limitation and cardiac autonomic function and whether cardiac autonomic function plays a role in exercise intolerance and daily physical activity (PA) in patients with COPD. Methods: Univariate and multivariate analyses were performed to evaluate the association between both 6-minute walking test (6MWT) and PA (steps per day) and pulmonary function, cardiac autonomic function (HR at rest, HRR and heart rate variability, HRV) in patients with COPD. Results: In 154 COPD patients (87 females, mean [SD]: age 62.5 [10.7] years, FEV1%predicted (43.0 [19.2]%), mean HR at rest was elevated (86.4 [16.4] beats/min) and HRV was reduced (33.69 [28.96] ms) compared to published control data. There was a significant correlation between FEV1 and HR at rest (r = -0.32, p < 0.001), between HR at rest and 6MWD (r = -0.26, p = 0.001) and between HR at rest and PA (r = -0.29, p = 0.010). No correlation was found between HRV and 6MWD (r = 0.089, p = 0.262) and PA (r = 0.075, p = 0.322). In multivariate analysis both HR and FEV1 were independent predictors of exercise capacity in patients with COPD. Conclusions: In patients with COPD the degree of airflow limitation is associated with HR at rest. The degree of airflow limitation and cardiac autonomic function, as quantified by HR at rest, are independently associated with exercise capacity in patients with COPD.

Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer

The aim of the present study was to investigate the prognostic value of tumor-infiltrated lymphocytes (TILs), especially the prognostic value of Foxp3+ regulatory T cells (Tregs), CD8+ CTLs and Tregs/CD8+ ratios in gastric cancer patients after R0 resection. From 133 patients, CD4+, CD8+ and Foxp3+ TILs were assessed by immunohistochemistry in tissue microarrays and N1 regional lymph nodes sections containing gastric cancer. The prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff, while the effects of Foxp3+/CD8+ ratios were evaluated using the value determined by ROC cure analysis as cutoff. It was found that CD4+ and CD8+ TILs were not associated with overall survival (OS). In the tumor sites, higher Foxp3+ Tregs/CD8+ ratio was an independent factor for worse OS (multivariate analysis HR = 2.827, P = 0.037). The 1-year, 2-year and 3-year OS rates were 90, 77.5 and 70% for the group with intratumoral high Tregs/CD8+ ratio, compared with 100, 94.3 and 90.5% for the group with intratumoral low ratio. At the same time, the presence of intratumoral high Foxp3+ Tregs was also associated with worse OS (log rank test, P = 0.025); however, it was not an independent predictor and correlated with intratumoral Foxp3+ Tregs/CD8+ ratio (chi(2) test, P < 0.001). Although the infiltration of Foxp3+ Tregs in N1 regional lymph nodes was associated with lymph node metastasis (P = 0.028), it was not associated with prognosis (P = 0.458). Intratumoral high Foxp3+ Tregs/CD8+ ratio was an independent predictor for the prognosis of gastric cancer. It can be inferred that a combination of deletion of Tregs and stimulation of CD8+ effector T cells may be an effective immunotherapy to prolong survival after surgery.

Significant Activity of Bortezomib-Based Therapy in Patients with Primary Systemic (AL) Amyloidosis

The use of bortezomib (B), a first-in-class proteasome inhibitor, administered with or without dexamethasone (D) for treatment of systemic AL amyloidosis, was reported in two small preliminary series to result in high rates of hematologic (HR) and organ (OR) response. We report here the efficacy and toxicity of bortezomib among 94 patients with AL amyloidosis attending three European amyloidosis centers. Consensus criteria were used for assessment of amyloidotic organ involvement and treatment response. Ninety-four patients treated with B±D were identified in the three centers' databases. Median age at start of treatment was 62 years. Eighty-one percent had received prior chemotherapy (median 2 lines, range 1–6), including high dose melphalan in 12% and a thalidomide combination in 55%; 69% had clonal disease that had been completely refractory. The median number of amyloidotic organs was 2 (range 1–5); the heart was involved in 73% (62% had symptomatic CHF) and the kidneys in 75% of cases. Median serum creatinine was 1.3 mg/dL (range 0.4–8.9), and 12% were dialysis-dependent. The median serum concentration of amyloidogenic free light chains (FLC) was 183 mg/L (range 9–9464); serum NT-proBNP was >332 ng/L and >1266 ng/L in 81% and 64% patients respectively. B was administered according to standard schedule in 80% and weekly in 20%. Median dose of D per cycle was 80 mg; 10% of patients received B without D. Median number of treatment cycles was 4 (range 1–8). HR was achieved in 71% of patients, including CR in 25%; 67% of responding patients did so by the 3rd month of treatment. HR was not related to prior treatment response although in untreated patients CR rates were higher (47% vs. 20%, p=0.074). In multivariate analysis HR was independently associated with age <65 years (HR 4.225, 95% CI 1.4–13, p=0.012) and biweekly administration of B (HR 5.63, 95% CI 1.3–24, p=0.02). HR rates with B+D were 17% higher than with B alone (p=0.074). A response of at least one amyloidotic organ was observed among 30% of patients: heart in 22%, renal in 17% and liver in 19%. OR was strongly associated with HR: 27 (43%) patients who had HR vs. 1 (3%) who did not met the criteria of HR, had response in at least one affected organ. Hematologic CR was associated with higher OR rates (64% vs. 32% for PR, p=0.001). In multivariate analysis higher rates of OR were associated with HR (HR 18.8, 95% CI 2.36–142, p=0.006); HR was strongly associated with cardiac response (46% vs.0%, p<0.001) and reduction 30% of NT-proBNP (84% vs. 27%, p<0.001). Estimated 1 and 2-year survival rates were 78% and 71% respectively with median follow-up of 12 months (range 0.5–48) from commencement of B. In multivariate analysis improved survival was independently associated with HR (HR: 0.15, 95% CI 0.041–0.551, p=0.004) and reduction of NT-proBNP by 30% (HR 0.10, 95% CI 0.025–0.424, p=0.001). Twelve month survival for patients who achieved both HR and an NT-proBNP response was 97%, compared to 83% for those who achieved either and only 24% for patients who achieved neither. On intent to treat basis, 50% of patients have progressed (hematologic in 31% and/or organ progression in 30%). Median time to any progression is 13.3 months (95% CI 9.1–17.5). Common toxicities included peripheral sensory neuropathy (40%, G2 in 30%), neuropathic pain (14%, G2 in 9%), hypotension/orthostasis (36%, G3 in 13%), and peripheral edema (33%, G3 in 12%). Grade 3 or 4 toxicity occurred in a total of 29% of patients; five (5%) deaths occurred within the first two months of treatment. These findings extend our preliminary observations and confirm that bortezomib-based treatment has substantial efficacy and manageable toxicity in patients with relapsed and refractory AL amyloidosis. Biweekly administration of bortezomib and the addition of dexamethasone may be related with higher rates of hematologic response. Reduction of NT-proBNP by >30% following B treatment was associated with survival benefit.

Focal Lesion (FL) Identification by MRI and Metastatic Bone Survey (MBS) in Multiple Myeloma (MM): Laboratory Correlates and Prognostic Implications for 611 Patients Receiving Total Therapy 2 (TT2).

Background: The Durie-Salmon staging system utilizes both laboratory features and information on MBS-FL. We hypothesized that, by detecting FL in the bone marrow prior to MBS-recognizable bone destruction, MRI would provide a biologically and clinically more relevant feature of FL-type MM (Tian et al, NEJM 2003).Patients and Methods: As part of a tandem transplant trial, TT2, MBS, MRI, clinical workup and cytogenetics were performed on 611 cases.Results: In a comparison of all areas imaged by both techniques, at least one FL was detected in 451 (74%) on MRI and 344 (56%) on MBS; 128 (21%) had no FL by either technique while 312 (51%) showed FL on both MBS and MRI. Importantly, of 267 patients without FL on MBS, 139 (52%) had FL on MRI; conversely, among 160 without FL on MRI, 32 (20%) had FL on MBS examination. The mean FL number among those with FL was 13 in case of MRI and 8 with MBS. Significantly higher proportions of patients had FL on MRI than MBS in spine (78% vs. 16% p<0.001), pelvis (64% vs. 28%, p<0.001) and sternum (24% vs. 3%, p<0.001). Higher FL number on both MRI and MBS and heterogeneity of the diffuse marrow signal on MRI STIR (indicating micro-nodular disease), cytogenetic abnormalities (CA), elevated serum levels of beta-2-microglobulin (B2M), C-reactive protein (CRP) and lactate dehydrogenase (LDH), in case of hypo-albuminemia and advanced age, were prognostically negative. On multivariate analysis (MVA), MRI- but not MBS-defined FL number was an independent adverse baseline feature for overall survival (HR=1.73; p<.001), independent of CA (HR=2.11; p<.001) and elevations of LDH (HR=1.56; p=.006) and B2M levels (HR=1.43; p=.026). Clinical complete response (CCR) (MVA HR=0.60; p=0.007) and MRI-CR (univariately: HR, 0.58; p=0.004) were favorable features when examined as time-dependent variables along with baseline features. Higher MRI-FL number (>7) was significantly associated with higher serum levels of LDH, CRP and creatinine as well as with hypo-albuminemia, whereas no correlations were noted with levels of B2M, bone marrow plasmacytosis, hemoglobin, CA, age, gender, race and Ig isotype.Conclusion: MRI examination in MM is justified:as an imaging tool that permits detection of FL long before osteolytic disease is recognized on MBS,as an independent staging tool with prognostic implications (that should replace MBS used in the Durie-Salmon staging system) after accounting for the presence of CA, LDH and B2M;as a means of documenting a superior state of CR (MRI-CR) conferring survival advantage, in patients with a high focal lesion number at baseline; and, not addressed here,as a tool for detecting and staging non-secretory and macro-focal MM, the latter often having minimal or no involvement on random bone marrow examination. [Display omitted]

Abdominal obesity and the risk of recurrent deep vein thrombosis

Background Abdominal obesity has been found to be associated with an increased risk of deep vein thrombosis (DVT). Whether patients with abdominal obesity have an increased risk of recurrence is currently unknown. Methods Patients with objective diagnosis of DVT and a life expectancy of greater than 6 months underwent measurement of the circumference of the waist. A waist circumference of greater than 102 cm for men and greater than 88 cm for women defined abdominal obesity. Information on age, gender, and on the presence of risk factors for DVT was collected. At follow-up, all patients underwent serial compression ultrasound of the lower limbs and were clinically evaluated every 6 months. Results One hundred patients were enrolled, 58 with abdominal obesity and 42 without. Mean age was 64.5 and 57.3 years, respectively ( p < 0.05). Percentage of male patients was 32.8% and 81.0% ( p < 0.01). Unprovoked DVT and transient risk factors rates were similar in both groups. Overall, recurrent DVT was documented in 29 patients, 16 in patients with abdominal obesity (27.6%) and 13 in patients without (31.0%). At the multivariate regression analysis HR for VTE recurrence in abdominal obese patients was 1.26 (95% confidence interval = 0.47–3.4). Conclusions Abdominal obesity does not seem to modify the risk of recurrent DVT.