Risk Factors For Shorter Overall Survival Research Articles

Prognostic Implications of 68Ga-FAPI-46 PET/CT-Derived Parameters on Overall Survival in Various Types of Solid Tumors.

Tumoral fibroblast activation protein expression is associated with proliferation and angiogenesis and can be visualized by PET/CT. We examined the prognostic value of [68Ga]Ga-fibroblast activation protein inhibitor (FAPI) (68Ga-FAPI)-46 PET/CT for different tumor entities in patients enrolled in 2 prospective imaging studies (NCT05160051, n = 30; NCT04571086, n = 115). Methods: Within 4 wk, 145 patients underwent 68Ga-FAPI-46 and [18F]FDG (18F-FDG) PET/CT. The association between overall survival (OS) and sex, age, tumor entity, total lesion number, highest SUVmax, and the presence of each nodal, visceral, and bone metastasis was tested using univariate Cox regression analysis. Multivariate analyses were performed for prognostic factors with P values of less than 0.05. Results: In the univariate analysis, shorter OS was associated with total lesion number and the presence of nodal, visceral, and bone metastases on 68Ga-FAPI-46 PET/CT (hazard ratio [HR], 1.06, 2.18, 1.69, and 2.05; P < 0.01, < 0.01, = 0.04, and = 0.02, respectively) and 18F-FDG PET/CT (HR, 1.05, 2.31, 1.76, and 2.30; P < 0.01, < 0.01, = 0.03, and < 0.01, respectively) and with SUVmax on 68Ga-FAPI-46 PET/CT (HR, 1.03; P = 0.03). In the multivariate analysis, total lesion number on 68Ga-FAPI-46 PET/CT was an independent risk factor for shorter OS (HR, 1.05; P = 0.02). In patients with pancreatic cancer, shorter OS was associated with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.09; P < 0.01) and bone metastases on 18F-FDG PET/CT (HR, 31.39; P < 0.01) in the univariate analysis and with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.04) in the multivariate analyses. In breast cancer, total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.02), as well as bone metastases on 18F-FDG PET/CT (HR, 9.64; P = 0.04), was associated with shorter OS in the univariate analysis. The multivariate analysis did not reveal significant prognostic factors. In thoracic cancer (lung cancer and pleural mesothelioma), the univariate and multivariate analyses did not reveal significant prognostic factors. Conclusion: Disease extent on 68Ga-FAPI-46 PET/CT is a predictor of short OS and may aid in future risk stratification by playing a supplemental role alongside 18F-FDG PET/CT.

Pan-cancer analysis of the oncogenic effects of G-protein-coupled receptor kinase-interacting protein-1 and validation on liver hepatocellular carcinoma.

Despite G-protein-coupled receptor kinase-interacting protein-1 (GIT1) being recognized as a new promoter gene in some types of cancer, its effect on human pan-cancers and liver hepatocellular carcinoma (LIHC) remains unclear. To elucidate the molecular mechanisms of GIT1 in pan-cancer and LIHC. Various bioinformatics approaches were utilized to elucidate the oncogenic effects of GIT1 on human pan-cancers. The GIT1 was aberrantly expressed in pan-cancers and associated with the clinical stage. Moreover, the upregulation of GIT1 expression was indicative of poor overall survival (OS) in patients with LIHC, skin cutaneous melanoma (SKCM) and uterine corpus endometrial carcinoma (UCEC), as well as of poor disease-free survival (DFS) in patients with LIHC and UCEC. Furthermore, GIT1 levels were correlated with cancer-associated fibroblasts (CAFs) in adrenocortical carcinoma (ACC), cervical squamous cell carcinoma (CESC) and LIHC. The analysis of single-cell sequencing data revealed an association of GIT1 levels with apoptosis, cell cycle and DNA damage. In addition, multivariate Cox analysis indicated that high GIT1 levels were an independent risk factor for shorter OS in patients with LIHC. Finally, the gene set enrichment analysis revealed INFLAMMATORY_RESPONSE pathway and IL2_STAT5_SIGNALING to be the most enriched in LIHC. Our data demonstrate the oncogenic effects of GIT1 on various cancers. We believe that GIT1 can serve as a biomarker for LIHC.

Preoperative Prognostic Nutritional Index Predict Survival in Patients With Resectable Esophageal Squamous Cell Carcinoma.

BackgroundPrognostic nutritional index (PNI) is one of the most important factors related to prognosis in many types of cancer. This study aimed to evaluate the PNI on predicting the overall survival (OS) in resectable esophageal squamous cell carcinoma (ESCC).MethodsA total of 165 patients with resectable ESCC were included in our retrospective study. PNI values before surgery were calculated for each patient [PNI = 10 × albumin (gr/dL) + 0.005 × total lymphocyte count (mm3)]. PNI cutoff value was selected by drawing receiver operating characteristics (ROC) curve, which used OS time as the endpoint. The Kaplan-Meier method and the Cox regression model of multivariate analysis were used to analyze the prognostic relationship between PNI and OS.ResultsAmong the 165 patients, 34 (20.6%) were women and 131 (79.4%) were men. The mean age was 62.67 ± 7.95 years, with the age range from 44 to 85 years. The average PNI was 46.68 ± 8.66. ROC curve showed that the best cutoff value was 43.85. All patients were divided into two groups: 72 patients (43.6%) were in the low PNI group (<43.85), while 93 patients (56.4%) were in the high PNI group (≥ 43.85). Univariate analysis demonstrated that PNI, tumor length, and T-stage and pathological stage were related to the prognosis of patients with ESCC (P <0.05). The Kaplan-Meier curve showed that the high PNI group has significantly increased OS compared to low PNI group (p = 0.01). Three-year OS rates were 57.5% in the low PNI group while 77.7% in the high PNI group. Univariate analysis showed that advanced pathological stage, large tumor length, and low PNI (separately, p < 0.05) were significant risk factors for shorter OS. Multivariate analysis showed that tumor length (P = 0.008) and PNI (P = 0.017) were independent prognostic factors in patients with resectable ESCC.ConclusionPNI is a simple and useful predictive marker for the OS time in patients with radical esophagectomy.

Prognostic significance of sarcopenia in patients with hepatocellular carcinoma treated with lenvatinib: A retrospective analysis.

Our study investigated the correlation between sarcopenia and clinical outcomes in patients with hepatocellular carcinoma (HCC) treated with lenvatinib. We retrospectively evaluated 40 consecutive patients with unresectable HCC receiving lenvatinib between November 2018 and May 2020 at the First Hospital of Jilin University. Skeletal muscle mass was measured before treatment initiation. Prognostic significance was assessed with univariate and multivariate Cox proportional hazards models. Overall survival (OS) and progression-free survival (PFS) were evaluated for patients with and without sarcopenia. Sarcopenia was present in 23/40 patients (57.5%). After a median follow-up of 9.2 months, patients with sarcopenia had significantly worse OS and PFS compared with those without sarcopenia (OS: 8.4 months [m] vs 14.7 m, P = .02; PFS: 4.2 m vs 9.0 m, P = .04). Multivariate Cox proportional hazards models identified presence of sarcopenia as an independent risk factor for shorter OS (hazard ratio [HR], 0.257; 95% confidence interval [CI], 0.083–0.794; P = .02). In subgroup analysis, sarcopenia was associated with worse survival than non-sarcopenic patients, irrespective of age, Barcelona clinic liver cancer stage, or albumin–bilirubin grade. Our results show sarcopenia may be a predictor of poor prognosis in patients with HCC receiving lenvatinib. Management of sarcopenia is a vital factor for improving survival outcomes in patients with HCC.

Circ_0000567/miR-421/TMEM100 Axis Promotes the Migration and Invasion of Lung Adenocarcinoma and Is Associated with Prognosis.

Purpose: Due to the high metastatic ability and poor prognosis of lung adenocarcinoma (LUAD), we identified novel non-coding RNAs, which constitute approximately 60% of human transcripts, as prognostic biomarkers and potential therapeutic targets for LUAD.Methods: In this study, we downloaded and analyzed microRNA (miRNA) datasets from The Cancer Genome Atlas (TCGA) to identify dysregulated miRNAs correlating with the overall survival (OS) of LUAD patients. miR-421, circ_0000567, and TMEM100 expression levels were examined by quantitative real-time polymerase chain reaction (qRT-PCR) in NSCLC tissues from 73 patients and adjacent normal tissues. Cell migration and invasion were assayed using wound healing and transwell assays. miR-421 target predictions were conducted using starBase, CircInteractome, circBank, TargetScan, miRanda, MirDB, miRpath, and Gene Expression Omnibus (GEO) databases. The circular structure and stability of circ_0000567 were verified by RNase R digestion and qRT-PCR using oligo(dT) and random primers. A luciferase reporter assay was used to evaluate the relationship between miR-421, circ_0000567, and TMEM100.Results: The miRNA panel associated with OS in patients with LUAD was screened according to the hazard ratio (HR) of miRNAs from high to low. Based on the correlation between these miRNAs and OS, as well as miRNA expression levels, miR-421 was selected for further outcome analysis. High miR-421 expression was an independent risk factor for shorter OS in 73 patients collected from our department. Bioinformatic analyses, luciferase reporter assays, and functional assays showed that circ_0000567 could act as a sponge for miR-421 and prevent it from directly targeting the 3'-untranslated region of TMEM100 mRNA and further degrading it in LUAD. miR-421 expression was significantly upregulated, while circ_0000567 and TMEM100 were downregulated in tumor tissues of LUAD, compared to their counterparts in normal tissues. Gain- and loss-of-function assays showed that miR-421 promoted LUAD cell migration and invasion. Overexpression of circ_0000567 inhibited migration and invasion, whereas co-transfection of circ_0000567 and miR-421 mimics partly counteracted this effect. TMEM100 was upregulated by enhanced circ_0000567 in LUAD cells, and the expression of TMEM100 was inversely proportional to miR-421, whereas it was directly proportional to circ_0000567 in 73 LUAD specimens, which confirmed the competitive endogenous RNA (ceRNA) network.Conclusion: Our findings suggest that miR-421 promotes the migration and invasion of lung adenocarcinoma via circ_0000567/miR-421/TMEM100 signaling and could be a prognostic biomarker for LUAD.

Prognostic significance of systemic inflammation score in patients who undergo hepatic resection for hepatocellular carcinoma

Systemic inflammation score (SIS) is a novel prognostic score (0, 1, or 2) for various cancers, based on preoperative serum albumin level and lymphocyte-to-monocyte ratio (LMR); modified SIS (mSIS) uses a different LMR cutoff value and was thought to be a more accurate predictor for cancer prognosis. Here, we assessed the prognostic value of SIS and mSIS in patients who receive hepatic resection for hepatocellular carcinoma (HCC). We retrospectively evaluated SIS and mSIS of 314 patients after hepatic resection for HCC, against their clinicopathological factors and outcomes, using receiver operating characteristics (ROC) analysis over time. Among patients with preoperative SIS 2, significantly more HCC specimens were poorly differentiated (P = 0.0281), larger (P = 0.0006), and had more microscopic vascular invasion (P = 0.0136) than the SIS 0-1 group; the mSIS 2 group also had significantly larger tumors (P = 0.0039) than the mSIS 0-1 group. In ROC analysis, SIS was a better predictor of overall survival (OS) and recurrence-free survival (RFS) than mSIS. The SIS 2 group had shorter OS (P = 0.0015) and RFS (P = 0.0065) than other patients. In multivariate analysis, SIS 2 was an independent risk factor for shorter OS (hazard ratio (HR) 1.53, P = 0.0497) and RFS (HR 1.58, P = 0.0053). SIS is superior to mSIS in predicting prognosis of patients with HCC. mSIS is not a great predictor of prognosis in resected HCC.

Predicting Factors for Oncological and Functional Outcome in Hypopharyngeal Cancer.

Hypopharyngeal squamous cell carcinoma (SCC) is a rare but aggressive malignancy, with low survival rates and high incidence of tumor and treatment-related morbidity. This study aims to analyze the long-term oncologic and functional outcomes of a large cohort of patients and to determine prognostic factors. Retrospective cohort study. The records of all patients diagnosed with hypopharyngeal SCC and treated with curative intent at our tertiary referral center were reviewed. Patient and initial disease characteristics, features, and complications of primary treatment, recurrence patterns, and corresponding treatments and the oncologic and functional long-term outcome were determined. For a total of 179 patients, primary radiotherapy (RT) was the predominant treatment modality (78%), whereas 22% underwent primary surgery. The median, 2-year, and 5-year overall survival (OS) for the study cohort were 47 months, 64% and 43%. The median survival after first and second relapse was 7 and 6 months, respectively. The 2 and 5-year relapse-free survival (RFS) was 52% and 36%. The median RFS after first relapse and salvage treatment was 9 months. A nodal status of ≥cN2 (HR = 1.89, CI:1.21-3.05, P < .005) and any other primary tumor localization than pyriform sinus (HR = 1.60, CI: 1.04-2.42, P < .05) were identified as independent risk factors for shorter OS and RFS. Regarding functional outcome, the 2- and 5-year laryngectomy-free-survival was 55% and 37%, respectively. In this large cohort with long-term follow-up, any other primary tumor localization than pyriform sinus and a nodal status of ≥cN2 were identified as risk factors for reduced OS and RFS. 4 Laryngoscope, 131:E1543-E1549, 2021.

Clinicopathologic features and prognostic value of KRAS, NRAS and BRAF mutations and DNA mismatch repair status: A single-center retrospective study of 1,834 Chinese patients with Stage I-IV colorectal cancer.

Mutations of KRAS, NRAS, BRAF and DNA mismatch repair (MMR) status have become an important part of the assessment of patients with colorectal cancer (CRC), while respective clinicopathologic features and prognostic significance in specific stages and related detection strategies remain unclear. We retrospectively analyzed clinicopathologic features and prognosis of 1,834 patients with Stage I–IV colorectal adenocarcinoma. Mutations in KRAS, NRAS and BRAF and DNA MMR status were determined. The mutation rates of KRAS, NRAS and BRAF were 46.4, 3.2 and 3.5%, respectively, and the mismatch repair gene deletion (dMMR) rate was 5.6%. In a multivariate analysis, female, advanced age, tumor type histology, mucinous carcinoma and positive tumor deposits were associated with a high KRAS mutation rate. A high BRAF mutation rate was associated with female, poor differentiation, lymphovascular invasion and positive tumor deposits. Factors associated with high dMMR rates included low age, large tumor size, poor differentiation, Stages I–III. Tumor site was independently associated with KRAS mutation, BRAF mutation and dMMR. KRAS and BRAF mutations were independent risk factors for shorter overall survival (OS) in Stage IV tumors but not in Stage I–III tumors. NRAS mutation was an independent risk factor for shorter OS in Stage I–II tumors. dMMR was independently associated with longer OS in Stage III tumors.

The impact of BMI extremes on disease-free survival and overall survival following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are increasingly being offered to patients with peritoneal carcinomatosis (PC). On the other hand, the prevalence of obesity is also increasing and expected to reach unprecedented rates in the upcoming decades. Therefore, managing patients on either extreme of the body mass index (BMI) range is anticipated to become a routine challenge and it becomes imperative to understand the impact of BMI, as a spectrum, on the long-term outcomes of CRS and HIPEC. We aim to study the short and long-term outcomes of CRS and HIPEC in patients on both extremes of the BMI spectrum. Patients with PC who underwent CRS and HIPEC over 10 years for ovarian, colorectal, and pseudomyxoma peritonei (PMP), and whose BMI was recorded were retrospectively included. Patients were divided based on their weight strata. The primary outcomes were disease-free survival (DFS) and overall survival (OS). A total of 126 patients were included. Fifty-seven point one percent were females and mean age was 59.31±1.57 years. No difference was noted between the groups in regards to demographics, perioperative characteristics, and immediate postoperative outcomes. Underweight group had a trend toward a higher peritoneal cancer index and lower rates of complete cytoreduction. Optimum BMI for OS and DFS was in the obesity range in colorectal PC, in the overweight range in ovarian PC, and in borderline obesity in PMP. Regression analysis identified underweight as an independent risk factor for shorter DFS, whereas underweight and morbid obesity were risk factors for shorter OS, after adjustment for other factors such as incomplete cytoreduction, tumor histology, and grade. OS and DFS vary across the BMI strata. Ovarian PC demonstrates earlier recurrence and shorter survival, whereas colorectal PC demonstrates the "obesity paradox" as patients move into the realm of obesity. BMI extremes, low or high, generally carry a poor prognosis for OS.

Elevated pretreatment platelet-to-lymphocyte ratio is associated with poor survival in stage IV non-small cell lung cancer with malignant pleural effusion

A higher platelet-to-lymphocyte ratio (PLR) has a clinical correlation with shorter survival in non-small cell lung cancer (NSCLC). The present study evaluated the association between the PLR and survival in patients with advanced NSCLC with malignant pleural effusion (MPE). Between January 2012 and July 2016, 237 patients with stage IV NSCLC were selected for evaluation. Receiver operating characteristic analysis was used to determine a cutoff for the PLR. Clinicopathological characteristics were compared between the high and low PLR groups, and the role of PLR as a predictive/prognostic maker was investigated. Among the 237 patients, 122 were assigned to the low PLR group and the other 115 to the high PLR group. According to multivariate analysis, male sex, not receiving active anticancer treatment, low hemoglobin level, low albumin level, high C-reactive protein level, and high PLR were identified as significant risk factors for shorter overall survival (OS) (p = 0.010, <0.001, 0.011, 0.004, 0.003, and <0.001, respectively). In the subgroup multivariate analysis of driver mutation-negative NSCLC, high Eastern Cooperative Oncology Group score, not receiving active anticancer treatment, low hemoglobin level, high C-reactive protein level, and high PLR were identified as significant risk factors for shorter OS (p = 0.047, <0.001, = 0.036, = 0.003, and <0.001, respectively). A high pretreatment PLR is independently associated with poor survival in stage IV NSCLC with MPE and in a subgroup of epidermal growth factor receptor and anaplastic lymphoma kinase wild-type NSCLC.

Impact of coexistent chronic obstructive pulmonary disease on the survival of patients with small cell lung cancer receiving chemotherapy.

BackgroundWhile there is growing interest in the correlation between chronic obstructive pulmonary disease (COPD) and non‐small cell lung cancer, very few studies have examined the interaction between COPD and small cell lung cancer (SCLC). Therefore, the aim of this study was to examine the impact of COPD on the survival of patients with SCLC.MethodsThe medical records of 110 patients with SCLC who received chemotherapy from July 2006 until April 2014 were retrospectively examined. The overall survival (OS) and progression‐free survival (PFS) rates of spirometry‐diagnosed COPD and non‐COPD groups were compared. Predictors for poorer survival were analyzed using Cox proportional hazards regression.ResultsOf the 110 SCLC patients, 57 (51.8%) had coexistent COPD. The median OS for the COPD group was 11.6 months and for the non‐COPD group was 11.2 months (log‐rank test, P = 0.581), whereas the median PFS rates were 6.65 and 6.57 months, respectively (log‐rank test, P = 0.559). Multivariate analysis identified Eastern Cooperative Oncology Group performance status ≥ 2 and extensive‐stage SCLC as independent risk factors for shorter OS; however, coexisting COPD was not a predictor of survival.ConclusionsAlthough over half of the SCLC patients receiving chemotherapy had COPD, coexisting COPD had no impact on the survival of patients with SCLC.

Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia

Background:In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols.Methods:Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR).Results:A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P=0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 (P=0.047) or BCR-ABL1 fusions (P<0.0001). In children, TP53mut was associated with lower OS (5-year OS: 50% vs 86%, P=0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P=0.009) and higher RR (5-year RR: 33.3% vs 18.6% P=0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P=0.04). In adults, TP53mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P=0.019) and a higher RR (5-year RR: 100% vs 61.4%, P=0.029), whereas JAK2mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P=0.035) and a higher RR (5-year RR: 100% vs 60.4%, P=0.002). TP53mut was an independent risk factor for shorter OS (HR=2.3; P=0.035) and, together with JAK2mut, also were independent markers of poor prognosis for RR (TP53mut: HR=5.9; P=0.027 and JAK2mut: HR=5.6; P=0.036).Conclusions:TP53mut and JAK2mut are potential biomarkers associated with poor prognosis in B-ALL patients.

Local Resection of Primary Tumor in Upfront Stage IV Breast Cancer

Background: This study aimed to identify the association of local surgery of the primary tumor in metastatic breast cancer (MBC) patients with overall survival (OS) and prognostic factors. Patients and Methods: Patients with primary MBC (1990-2006) were included in our retrospective analysis (n = 236). 83.1% had surgery for the primary tumor. OS was evaluated using Kaplan-Meier estimates. Predictive factors for OS were determined. Results: Median follow-up was 123 months for all patients still alive at the time of analysis. In univariate analysis, patients with surgery of the primary tumor had significantly prolonged OS (28.9 vs. 23.9 months). Within the surgery group, patients with MBC limited to 1 organ system had a better outcome (39.3 vs. 24.9 months), as did asymptomatic patients. Independent risk factors for shorter OS were hormone receptor negativity, symptoms, and involvement of ≥ 1 organ system. Conclusion: Patient selection for local therapy was confounded by a more favorable profile and a lesser tumor burden before surgery, which might implicate a bias. Nevertheless, our univariate results indicate that local surgery of the primary tumor in MBC patients could be considered as part of the therapeutic regimen in selected patients. However, larger patient numbers are needed to prove these findings in the multivariate model.

Epidemiological profile and prognostic factors in patients with lung cancer

To describe the epidemiological profile of patients with lung cancer treated at a public tertiary referral hospital specializing in oncology, and to explore variables that may be related to the overall survival (OS) of these patients. Data from the medical records of all patients with invasive lung cancer consecutively seen at the Oncology Department of Hospital Estadual Mário Covas between August 2008 and December 2013 were extracted. The information obtained was submitted to statistical analysis. Of the total 210 patients, 39 were excluded from analysis due to lack of information in the medical record. The most common histological type was adenocarcinoma, representing 39.41% of the sample, followed by squamous cell carcinoma with 25.29% and small-cell carcinoma with 13.53%. Other histological types were responsible for the remaining 21.76%. There was a statistically significant association between Karnofsky performance status (KPS) ≤ 70%, palliative chemotherapy lines performed and stage at diagnosis, and OS. Additionally, administration of target therapy to patients with EGFR mutation was associated with significantly better overall survival. However, analysis of laboratory variables (hemoglobin, albumin and LDH) as possible prognostic factors for survival showed no statistically significant relationship. Among patients with stage III and IV, the median OS was 10.1 months. The risk factors for shorter OS were KPS score ≤ 70%, less than two lines of palliative chemotherapy, and stage III and IV at diagnosis. The implementation of CT screening for risk patients may allow earlier diagnosis of cases and improve these results.

A clinical-based risk score for decision making for surgery after induction chemotherapy in malignant pleural mesothelioma patients.

7587 Background: Scoring tools predicting the potential benefit from surgery after induction chemotherapy in mesothelioma patients may influence decision making. Our score is based on 4 clinical variables available before surgery. Methods: 128 patients were uniformly treated with cisplatin based induction chemotherapy followed by extrapleural pneumonectomy between 1999 and 2011. Based on clinical experience and survival influencing factors resulting from uni-and multivariate analysis, we designed a risk score. All 4 variables building up the score were available for 59 patients: pre chemotherapy volumetry above 500 ml, non-epithelioid histotype in the diagnostic biopsy, pre chemotherapy CRP value above 30 mg/l and progressive disease after chemotherapy according to modified RECIST criteria. The 5 resulting groups were analyzed for overall survival (OAS) and progression free survival (PFS) using Kaplan-Meier and Cox regression model. Results: The score strongly stratified patients into high and low risk groups for shorter OAS (Table) (p&lt;0.0005). As to PFS, patients with Score 0 also had significantly longer median PFS (16 months; 95% CI: 12; 20) in comparison to patients with score 3 or higher (6 months; 95% CI: -; -) (p&lt;0.0005). In Cox regression analysis the risk factor for shorter OAS and PFS increased correspondingly to our score. Conclusions: Our new score based on 4 clinical variables available before surgery identifies patients’ subgroups who may benefit from surgery after induction chemotherapy, which will be further assessed prospectively. [Table: see text]

Allogeneic Hematopoietic Stem-Cell Transplantation Using Fludarabine/Treosulfan Conditioning Regimen Compared with Busulfan-Based Myeloablative and Reduced-Intensity Conditioning in Patients with AML and Mds; Relative Outcomes Depend On Disease Status at Transplantation.

Abstract 3358Poster Board III-246Allogeneic stem-cell transplantation (SCT) with both myeloablative (MAC) and reduced-intensity conditioning (RIC) is effective therapy in AML and MDS. However, the relative merits of each may differ in different settings. We have previously reported on the role of dose intensity in a group of 112 patients (pts) with AML/MDS given allogeneic SCT with different busulfan (Bu)- based regimens (Leukemia 2006). We showed that survival was similar with MAC and RIC in pts given SCT in remission, but was inferior in pts given RIC in active disease due to high post transplant relapse rates. The combination of fludarabine and treosulfan (FT) has been reported as an effective regimen in AML/MDS with limited toxicity. However, the relative dose intensity and expected outcomes with FT in the different SCT settings, compared with Bu-based regimens is not well defined. We now extend the analysis to a group of 298 pts with AML/MDS, given allogneic SCT from sibling (n=153) or unrelated/mismatched donors (n=145) and included the more recently introduced FT regimen. Pts meeting standard eligibility criteria for myeloablative conditioning were given high dose iv Bu and cyclophosphamide (BuCy, n=81). Pts with a risk factor for MAC, mainly due to advanced age, were given fludarabine (F) and reduced doses of Bu (6.4 mg/kg, FB2, n=91), F with high dose Bu (12.8 mg/kg, FB4,n=63) or FT (treosulfan 30-36 gr/m2). Protocol allocation was not randomized, resulting in a younger age for pts in the BuCy group; median age 37 years compared with 60, 50, and 58 for FB2, FB4 and FT, respectively. BuCy and FT groups included more pts with active disease at SCT, while the BuCy group had less unrelated donors. Non-relapse mortality (NRM) was 17%,18%,18% and 20% with FB2,FB4,FT and BuCy, respectively (p=NS). However, pts were selected to regimens other than BuCy based on a high estimated risk for NRM. With a median follow-up of 38 months (range, 1-115), estimated 5-yr overall survival (OS) was 38% (95%CI, 31-44). OS rates were 36%,33%,43% and 41% after FB2, FB4, FT and BuCy, respectively (p=NS). Multivariate analysis (MVA) defined age>50 [HR 1.5 (1-2.2), p=0.05)], active disease at SCT [HR 2.3 (1.6-3.2), p<0.001)] and unrelated donor [HR 1.5 (1-2.0), p=0.02)], as risk factors for shorter OS. The conditioning regimen used was not predictive in the entire group. When the analysis was limited to pts in first or subsequent remission (n=126), OS was 51%,43%,58%, and 43%, respectively. MVA identified age>50 as an adverse factor, while SCT using FB2 or FT was associated with prolonged OS [HR 0.3 (0.2-0.7), p=0.002)]. When the analysis was limited to pts with active disease (n=172) either chemo-refractory to induction or subsequent therapy (n=93) or untreated [n=79; untreated relapsed AML (n=15) or MDS with excess of blasts (n=64)], OS was 12%,25%,32%, and 36%, respectively. MVA identified chemo-refractory disease as the major adverse factor; OS [HR 2.2 (1.5-3.3), p=0.001), while SCT using BuCy or FT was associated with prolonged OS [HR 0.7 (0.5-1.0), p=0.06)]. The advantage of FT was observed mainly in pts with active untreated disease (mostly MDS). OS was 57% (95%CI, 32-82) in a group of 25 pts given FT for advanced, previously untreated MDS. Only BuCy and to a lesser degree FB4 (OS 27%) were effective in the truly refractory pts. FB2 and FT, were associated with a grim outcome in this setting (OS 6%, p=0.04). In conclusion, dose intensity is associated with different outcomes in the different transplant setting. In pts in remission at SCT, outcome is mostly related to SCT toxicity, thus there is an advantage to less intensive regimens, such as FB2, while FT shares this characteristic. When outcome is dominated by the risk for relapse, such as in pts with active disease at SCT, there is an advantage to a more intensive regimen, such as BuCy. FT shares this characteristic mainly in pts with no true chemo-refractoriness, and has an advantage over FB2 in this setting. FT should be considered as a reduced toxicity myeloablative conditioning, that is feasible in pts ineligible for MAC, rather than a reduced-intensity regimen. In pts in CR toxicity is comparable to FB2 while in pts with active untreated MDS its anti leukemic activity is comparable to BuCy. Disclosures:No relevant conflicts of interest to declare.

Clinical Outcome of B-Cell Chronic Lymphocytic Leukemia Following Alemtuzumab Therapy: Retrospective Study within Various Cytogenetic Risk Categories

B-cell chronic lymphocytic leukemia (CLL) with 17p deletion responds poorly to chemotherapeutic agents. This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced CLL, categorized by cytogenetic profile.Methods: This is the largest data base with efficacy analysis of alemtuzumab in CLL stratified according to cytogenetics. Detailed data analysis was done in 138 CLL patients, in whom cytogenetic analysis was performed by FISH using the standard CLL analysis categorized according to Doehner et al. (N Engl J Med 343, 1910; 2000). Responses were evaluated according to the NCI criteria; progression-free survival (PFS) and overall survival (OS) were also assessed.Results: 73% of the patients were male. At start of alemtuzumab therapy, the median age was 64 years (range, 46–92); 12% were in Rai stage I, 18% in stage II, 20% in stage III, and 50% in stage IV. The median number of two prior therapies was 2 (range, 0–10); of the patients who received prior fludarabine (F) (n=113), 70% were F-refratory, 25% sensitive, and in 5% this was unknown. 30% and 17% of patients had bulky lymphadenopathy (>5 cm) and giant splenomegaly (>20 cm), respectively. Cytogenetic abnormalities were as follows: 13q deletion 14%; trisomy 12, 12%, 11q deletion 20%; 17p deletion, 33%, none of these, 22%. The overall response rate (ORR) was 38% in the total cohort. ORR was 53%, 56%, 21%, and 44% in the subgroup of 13q deletion, trisomy 12, 11q deletion, and 17p deletion, respectively; patients without any of these abnormalities had an ORR of 27%. From start of alemtuzumab, median PFS and OS for the whole cohort was 6.9 months and 30 months, respectively. Notably, PFS and OS in 17p deletion patients was 7.1 months and 19.1 months, respectively, an encouraging outcome when considering the unfavourable risk profile in these patients. In 17p deletion patients, response was remarkable also in disease involved lymph nodes (78%). Patients with F-resistant disease and 17p deletion, an extraordinarily poor prognostic group (n=25), had encouraging ORR, PFS, and OS rates (28%; 7.2 months; and 19.1 months, respectively), which did not differ from those in F-resistant patients with good risk cytogenetics. In a multivariate Cox regression analysis, independent risk factors for shorter OS were anemia (hazard ratio [HR] = 2.48; 95% CI, 1.50–4.11; P <.001), ≥3 of prior lines of therapy (HR = 2.00; 95% CI, 1.24–3.24, P =.005), and poor risk cytogenetics ([17p deletion and 11q deletion], HR = 2.23; 95% CI 1.35–3.69, P =.002).Conclusion: Alemtuzumab was effective in CLL across all cytogenetic categories evaluated. In patients with favorable cytogenetics, we observed that alemtuzumab is a highly effective therapy even when conventional chemotherapy has failed. Patients with 17p deletion achieved quite favorable ORR and OS upon alemtuzumab. Thus, the 17p deletion group can often be shifted to an “intermediate” risk CLL, and responding patients are frequently re-treated with alemtuzumab.