We conducted a retrospective record review to determine the frequency of venous thromboembolism (VTE) in patients with diffuse large B-cell lymphoma (DLBCL). All records from 1990 to 2001 of patients ...with the diagnosis of DLBCL at a tertiary care hospital were reviewed. Those with transformation from low-grade lymphoma, central nervous system lymphoma, HIV-related lymphoma or with incomplete records were excluded. All episodes of symptomatic VTE confirmed by imaging studies that were either present at diagnosis or occurred during initial treatment were identified. VTE occurred in 27 of 211 patients (12.8%). Stage I disease was associated with a low risk, whereas a high international prognostic index score increased risk. Of patients with VTE, thrombosis was present at diagnosis in 37% and occurred during the first chemotherapy cycle in 22% and during the first three cycles in 82%. The median survival of patients with VTE was 1.04 years 95% confidence interval (CI) = 0.75 - 1.33 compared to 5.2 years (95% CI 1.8 - 8.6) for those without VTE (P = 0.038). We conclude that VTE is a frequent complication of DLBCL that occurs particularly at diagnosis and during initial therapy, and it is associated with a worse prognosis.
To systematically review: 1) peri-extubation settings; and 2) association between peri-extubation settings and outcomes in preterm neonates.
In this systematic review, studies were eligible if they ...reported patient-data on peri-extubation settings (objective 1) and/or evaluated peri-extubation levels in relation to clinical outcomes (objective 2). Data were meta-analyzed when appropriate using random-effects model.
Of 9681 titles, 376 full-texts were reviewed and 101 included. The pooled means of peri-extubation settings were summarized. For objective 2, three experimental studies were identified comparing post-extubation CPAP levels. Meta-analyses revealed lower odds for treatment failure pooled OR 0.46 (95% CI 0.27-0.76); 3 studies, 255 participants but not for re-intubation pooled OR 0.66 (0.22-1.97); 3 studies, 255 participants with higher vs. lower CPAP.
Summary of peri-extubation settings may guide clinicians in their own practices. Higher CPAP levels may reduce extubation failure, but more data on peri-extubation settings that optimize outcomes are needed.
Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator ...of transcription pathway in the pathogenesis and clinical course of pancreatic cancer.
In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m(2) twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation.
In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation-based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%).
Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation.
Lessons Learned
Itacitinib in combination with nab‐paclitaxel plus gemcitabine demonstrated an acceptable safety profile with clinical activity in patients with advanced solid tumors including ...pancreatic cancer.
The results support future studies of itacitinib as a component of combination regimens with other immunologic and targeted small molecule anticancer agents.
Background
Cytokine‐mediated signaling via JAK/STAT is central to tumor growth, survival, and systemic inflammation, which is associated with cancer cachexia, particularly in pancreatic cancer. Because of their centrality in the pathogenesis of cancer cachexia and progression, JAK isozymes have emerged as promising therapeutic targets. Preclinical studies have demonstrated antiproliferative effects of JAK/STAT pathway inhibition in both in vitro and in vivo models of cancer, including pancreatic cancer.
Methods
This phase Ib/II dose‐optimization study assessed itacitinib, a selective JAK1 inhibitor, combined with nab‐paclitaxel plus gemcitabine in adults with treatment‐naïve advanced/metastatic disease (Part 1) or pancreatic adenocarcinoma (Parts 2/2A; NCT01858883). Starting doses (Part 1) were itacitinib 400 mg, nab‐paclitaxel 125 mg/m2, and gemcitabine 1,000 mg/m2. Additional dose levels incorporated were granulocyte colony‐stimulating factor, de‐escalations of itacitinib to 300 mg once daily (QD), nab‐paclitaxel to 100 mg/m2, and gemcitabine to 750 mg/m2.
Results
Among 55 patients in Part 1, 6 developed seven hematologic dose‐limiting toxicities (Cycle 1). Itacitinib 300 mg plus nab‐paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 was tolerated and expanded in Part 2. Treatment discontinuation and grade 3/4 neutropenia rates prompted itacitinib de‐escalation to 200 mg QD in Part 2A. The most common grade 3/4 toxicities were fatigue and neutropenia. Partial responses occurred across all itacitinib doses and several tumor types (overall response rate, 24%).
Conclusion
Itacitinib plus chemotherapy demonstrated acceptable safety and clinical activity in patients with advanced solid tumors including pancreatic cancers. This study was terminated early (sponsor's decision) based on negative phase III results for a JAK1/2 inhibitor in previously treated advanced pancreatic cancer.
经验获取
• Itacitinib 和白蛋白结合型紫杉醇及吉西他滨联合治疗在晚期实体肿瘤(包括胰腺癌)患者中显示出可接受的安全特性与临床活性。
• 研究结果支持将 Itacitinib 作为含有其他免疫和靶向小分子抗癌剂的联合治疗的组成部分开展未来研究。
摘要
背景。通过 JAK/STAT 的细胞因子介导信号传导对于肿瘤生长、生存以及与癌症恶病质(特别是胰腺癌)相关的系统性炎症而言,至关重要。由于 JAK 同工酶在癌症恶病质和癌症进展的致病机制中具有重要地位,它们现已成为有希望的治疗靶点。临床前研究已经证明 JAK/STAT 通路抑制在癌症(包括胰腺癌)的体外和体内模型中具有抗增殖作用。
方法。本次 Ib/II 期剂量优化研究对既往未接受治疗的晚期/转移性癌(第 1 部分)或胰腺癌(第 2/2A 部分;NCT01858883)成年患者的 Itacitinib(一种选择性的 JAK1 抑制剂)和白蛋白结合型紫杉醇及吉西他滨联合治疗进行了评估。初始剂量(第 1 部分)为 Itacitinib 400 mg,白蛋白结合型紫杉醇 125 mg/m2,吉西他滨 1 000 mg/m2。加入的额外剂量是粒细胞集落刺激因子,Itacitinib 降至 300 mg,每天给药一次 (QD),白蛋白结合型紫杉醇降至 100 mg/m2,吉西他滨降至 750 mg/m2。
结果。在第 1 部分中的 55 名患者中,有 6 名患者出现七次血液学剂量限制性毒性(第 1 周期)。在第 2 部分中,可以耐受和扩展 Itacitinib 300 mg 和白蛋白结合型紫杉醇 125 mg/m2 及吉西他滨 1 000 mg/m2 联合治疗。在第 2A 部分中,治疗终止以及 3/4 级嗜中性粒细胞减少症比率导致 Itacitinib 降至 200 mg QD。最常见的 3/4 级毒性为疲劳和嗜中性粒细胞减少症。部分缓解在所有 Itacitinib 剂量和几种肿瘤类型中均有出现(总缓解率为 24%)。
结论。Itacitinib 联合化疗在晚期实体肿瘤(包括胰腺癌)患者中显示出可接受的安全性与临床活性。基于 JAK1/2 抑制剂在经治的晚期胰腺癌中的阴性 III 期结果,本研究提前终止(由申办方决定)。
Introduction: Patients with recurrent or refractory Hodgkin (HL) and non-Hodgkin lymphoma (NHL) treated with high dose chemotherapy and autologous stem-cell rescue (ASCR) commonly relapse (post-ASCR) ...(70–90%) in sites of previous disease. Although adjuvant involved field radiation therapy (IFRT) to sites of previous recurrence might be expected to enhance local control, translation of this into improved disease-free (DFS) or overall survival (OS) is controversial. We sought to evaluate IFRT following ASCR in terms of patterns of recurrence, OS and DFS.
Methods and Materials: All 281 patients with recurrent or refractory HL and NHL who underwent ASCR between 5/92 and 7/03 were analyzed. Disease stratification at the time of transplant included HL, 24%, aggressive NHL (ANHL) 62%, and indolent NHL (INHL) 14%. Most, 46% underwent ASCR after 1st relapse, 18% after 2nd relapse, 4% after 3rd relapse and 26% had refractory disease at ASCR. IFRT was administered to 129 patients (46%). Physician and patient choice determined which patients received IFRT. Dose ranged from 20–36 Gy depending on response to salvage therapy before ASCR and the presence of visible imaging abnormalities following ASCR. For end point analysis 39 patients (14%) including 11 HL, 23 ANHL, and 5 INHL had insufficient data and were excluded.
Results: Mean follow-up was 3 years (.3 – 12). The median age at ASCR was 45 years (8 – 73). Male to female ratio was 1.3:1. Thirty five percent of patients had prior RT. On univariate analysis, OS and DFS following IFRT for ANHL was superior (or approached this statistically) at 5 years. For HL, improved OS approached significance, whereas DFS did not despite an apparent benefit by disease-free percentages. IFRT appears to be disadvantageous in INHL, but patient numbers were very small. OS and DFS at 5 years are in the table.
Survival Table5-year OS (%)5-year DFS (%)HLWith IFRT6279Without IFRT3768p-value.07.41Aggressive NHLWith IFRT5765Without IFRT3749p-value.02.07Indolent HNLWith IFRT5067Without IFRT8588p-value.06.30
On multivariate analysis, for ANHL, IFRT was protective (p = .002, Hazard Ratio = 0.39) and bulky disease was adverse (p = .04, HR = 2.04). For HL, an advantage of IFRT did not reach statistical significance (p = .63, HR = .8). For INHL, IFRT was associated with an inferior outcome (p = .23, HR = 4.9).
Conclusion: Recognizing that bias exists in patient selection for IFRT post-ASCR (in both directions), a survival benefit appears to exist for patients with ANHL, and potentially for those with HL. The absence of a difference in DFS may relate to relapses in other sites or competing events with censored data. Longer follow-up or larger patient numbers are necessary to confirm a long- term improvement. INHL did not benefit from IFRT as might be expected since this group is more likely to have occult disseminated, chemotherapy insensitive disease. Determination of specific patterns of disease recurrence is in progress.
Purpose/Objective: To evaluate patterns of recurrence in patients with Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL) who subsequently undergo autologous stem cell transplant (ASCT). In this ...population that has declared itself as high risk, we evaluated time to and sites of relapse relative to initial sites of disease and radiation therapy (RT). This information might enhance understanding of the natural history of these diseases in the setting of modern therapy, influence treatment strategies, and assist in screening decisions.
Materials/Method: We analyzed the records of all 281 consecutive patients with refractory or recurrent HL and NHL (indolent and aggressive, as defined at initial diagnosis) who underwent ASCT in our center between 5/92–7/03. Patients were initially diagnosed between 1979–2003 at a median age of 44 years (8–70). 25 patients were unevaluable due to insufficient data, and 68 patients were excluded from analysis because their disease was refractory to initial and salvage therapy. HL patients were segregated according to initial staging (I/II vs. III/IV).
Results: Early stage HL patients relapsed at a median of 2.0 years (0.5–10.3) with 87% relapsing in initial disease site(s); 13% (95% CI 3.8–30.1%) relapsed only in new sites. Advanced stage HL patients relapsed at a median of 1.4 years (0.6–10.5) with 96% relapsing in initial site(s); 4% (95% CI 0.1–21.9%) relapsed only in new sites. Indolent histology NHL patients relapsed at a median of 2.1 years (0.5–14.9) with 83% relapsing in initial site(s); 17% (95% CI 7.3–32.8%) relapsed only in new sites. Aggressive histology NHL patients relapsed at a median of 1.0 year (0.3–8.0) with 64% relapsing in initial site(s); 36% (95% CI 26.2–46.2%) relapsed only in new sites. For early stage HD patients, recurrences were predominantly local, and uniformly so in those unirradiated. For all other groups, fewer patients were irradiated than unirradiated and local recurrences predominated regardless of therapy.
Conclusions: Almost all patients with HL who relapse and subsequently undergo ASCT initially recur in previous disease sites. Although patients with aggressive histology NHL are more likely to relapse in new sites than patients with indolent NHL, local recurrences predominate in both groups. The median time to recurrence is brief (1–2.1 years). In a population defined by recurrent disease, it is expected that relapses will occur in irradiated sites. Relative protection by RT of local recurrence cannot be determined until all patients, regardless of relapse status, are analyzed. However, these data support an emphasis on local control and suggest that the frequency of screening be most rapid in the early post-therapy years.
Comparison of Site(s) of Relapse to Site(s) of Initial PresentationHLNHLEarly (n=30)Adv. (n=23)Ind. (n=40)Agg. (n=95)Characteristic%%%New Site(s)1341836Previous site(s) only63616044Previous site(s) + new site(s)23352320CharacteristicnnnnRadiated patients relapsing in previous site(s)15/196/65/720/34Unradiated patients relapsing in previous site(s)11/1116/1726/3342/61
Background: Venous thromboembolism (VTE) is a significant complication of cancer and particularly of newer anti-cancer therapies. The risk of VTE is estimated to be 0.04%/month (0.5%/year) in cancer ...patients. We conducted a prospective analysis to determine the frequency and risk factors for symptomatic VTE in cancer patients actively receiving chemotherapy.
Methods: The Awareness of Neutropenia in Cancer (ANC) Study Group is currently enrolling patients with breast, lung, colon, ovary and other cancers, at 137 sites nationwide, with an accrual goal of 4,500 patients. Patients are registered at the time of initiation of a new chemotherapy regimen, and followed for the duration of 4 cycles. The association of VTE with clinical variables was studied in univariate analysis and in a multiple logistic regression model. No significant first-order interactions were observed between the variables in this model. A risk score for VTE was estimated for each subject from the weighted sum of model predictor variables from the multivariate model.
Results: A total of 2,151 patients treated with at least one cycle of chemotherapy were available for analysis. Pulmonary embolism occurred in 11, and deep venous thrombosis in 35, for a VTE incidence of 2.14 % over median follow-up of 2.5 months (0.85%/month). Incidence of first VTE event was greatest in cycles 1 (0.93%/cycle) and 2 (0.88%/cycle), and declined in cycle 3 (0.53%/cycle). Incidence varied significantly by site of disease (p=0.01) with highest rates in patients with upper gastrointestinal (2.4%/month) and lung cancers (1.2%/month), and lymphomas (1.2%/month). Other clinical variables associated with development of VTE in univariate analysis included baseline platelet count ≥350,000, an ECOG PS ≥ 2, and baseline use of erythropoietin or colony-stimulating factors. Patients with VTE reported a chemotherapy delay of ≥ 7 days in 40% compared to 23.6% in patients without VTE (OR 2.15, p=0.01). Based on the results of the multivariate model (c statistic=0.73.65,.81) the population was divided into low, intermediate and high-risk based on tertiles of risk scores. Patients deemed high-risk had a VTE risk of 1.5%/month, which was a six-fold increase compared to those deemed low-risk (see Table).
Conclusion: Symptomatic VTE is much more frequent in cancer patients on chemotherapy than previously estimated, even in patients with hematologic malignancies. VTE is associated with a nearly two-fold risk of significant delay in chemotherapy, which could impact on cancer outcomes. This is the first prospectively generated predictive model for chemotherapy-associated thrombosis, and can be used to define a high-risk study population for trials of thromboprophylaxis.
Incidence of Chemotherapy-Associated VTE By Risk Categories
Risk ScoreNVTE eventsObserved VTE Incidence(%)Predicted VTE Incidence(%)Low64840.62(0.24/month)0.58(0.23/month)Intermediate702101.42(0.56/month)1.48(0.59/month)High799303.75(1.5/month)3.73(1.49/month)
Background:
Venous thromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE) is a well-known complication of cancer. VTE frequency varies according to the underlying ...malignancy. Diffuse large B cell Lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL). VTE during initial treatment of DLBCL is a complication recognized by treating physicians. Little information is available regarding the frequency of VTE and its association with outcomes in DLBCL. We conducted a retrospective cohort study to determine the frequency and timing of VTE during initial treatment of DLBCL, as well as identifying risk factors associated with VTE, and the clinical impact of VTE on survival.
Methods:
We reviewed records of consecutive patients diagnosed with de novo DLBCL seen at University of Rochester from January 1990 to December 2001. Patients with transformed DLBCL, CNS lymphoma, HIV-related NHL, and patients whose complete records were unavailable were excluded. We considered only episodes of VTE that occurred during the initial treatment of DLBCL. For analysis of risk factors for VTE, Chi-square test or Fisher's exact test was used to compare the categorical variables and t-test was used to compare continuous variables. Kaplan-Meier estimate was used to compare overall survival between patients with or without VTE. Log-rank test was used to compare statistical differences between survival curves.
Results:
A total of 211 patients with DLBCL were included. VTE occurred in 27 patients (12.8%). DVT occurred in 22, PE occurred in 3, and both DVT and PE in 2. Of all VTE, 37% occurred at diagnosis of DLBCL, and 82% in the first three cycles of treatment. VTE involved the lower limb in 44%. Baseline characteristics were similar between patients with or without VTE regarding age, sex, race, ECOG performance status, histology, B symptoms, LDH, and bone marrow involvement. Fewer patients with VTE, however, were stage I compared to the no VTE group (3.7% vs 27.3 %, P = 0.017). Furthermore, patients with VTE were more likely to be in the high-risk international prognostic index (IPI) category (29.6% vs 10.3%, P = 0.048). Median survival time for patients with VTE was 1.04 years (95% CI 0.75–1.33) compared to 5.2 years for patients with no VTE (95% CI 1.8–8.6) (Log rank test, P = 0.038).
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Conclusion:
VTE is a frequent complication of initial treatment of DLBCL. The majority of cases occur at diagnosis or during the first three cycles of treatment. High-risk IPI is associated with increased incidence of VTE during initial treatment of DLBCL. VTE is a poor prognostic factor and is associated with inferior survival. Clinical trials of thromboprophylaxis are warranted.
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