Probability Of Disease-free Survival Research Articles

A case study of aging intensity function on censored data

A major concern for applied statisticians is the analysis of survival experiments under censoring. Here we study the aging intensity function and the hazard rate function on a case study of bone marrow transplant in acute leukemia patients, based on right-censored data. We focus on disease-free survival probabilities of patients grouped into risk categories namely, ALL (acute lymphoblastic leukemia), AML (acute myeloctic leukemia) low risk, AML high risk patients.

Peripheral Blood or Bone Marrow Stem Cells? Practical Considerations in Hematopoietic Stem Cell Transplantation.

Although peripheral blood stem cells (PBSC) have worldwide become the predominant source of progenitor cells for hematopoietic stem cell transplantation (HSCT), debate about their role compared with bone marrow (BM) has recently intensified, in large part based on the results of a multicenter Clinical Trials Network study which showed lower incidence of chronic graft-versus-host disease (cGVHD) and improved quality of life in recipients of myeloablative HLA-matched unrelated BM compared with PBSC transplants. However, in certain patient populations, PBSC may lead to improved clinical outcomes due to faster hematologic recovery, a lower risk of graft failure, and possibly a lower probability of relapse. This review will provide a comprehensive summary of studies comparing PBSC with BM as the graft source in terms of acute and chronic GVHD incidence, time to engraftment, and disease-free and overall survival probabilities after HLA-matched related and unrelated donor transplantation and haploidentical donor transplantation. Recommendations based on these studies regarding the use of PBSC versus BM for HSCT are offered.

Prognostic Value of Inflammatory Biomarkers in Gastric Cancer Patients and the Construction of a Predictive Model

Background: It is known that inflammation promotes cancer development. However, a few studies have evaluated the prognostic significance of inflammatory biomarkers in gastric cancer (GC). Methods: In this study, 2,334 patients who underwent gastrectomy for GC at Fudan University Shanghai Cancer Center between 2003 and 2007 were retrospectively analyzed, and 1,227 patients were found to be eligible. The preoperative serum neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR), and albumin/globulin ratio (AGR) levels were analyzed. A nomogram was constructed with the Cox proportional hazards regression model in the training set (n = 818) to predict the probability of overall survival (OS) and disease-free survival (DFS). The predictive accuracy and discriminative ability were determined using the concordance index (C-index) and calibration curve. Results: We found that lower AGR and LMR values were correlated with decreased OS, lower LMR values, and higher NLR values with a decreased DFS. Other significant factors were included to construct the nomogram. The discriminative ability of the nomogram was higher than that of the eighth American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system (0.746 for TNM v.s. 0.654 for the nomogram, p < 0.001). Conclusions: The nomogram yielded a more accurate prognostic prediction in GC patients after gastrectomy, suggesting great clinical value.

Prognostic value and potential function of splicing events in prostate adenocarcinoma.

Prostate adenocarcinoma (PRAD) is one of the most common types of malignancy in males and at present, effective prognostic indicators are limited. The development of PRAD has been associated with abnormalities in alternative splicing (AS), a requisite biological process of gene expression in eukaryotic cells; however, the prognostic value of AS products and splicing events remains to be elucidated. In the present study, the data of splicing events and the clinical information of PRAD patients were obtained from The Cancer Genome Atlas (TCGA)SpliceSeq and TCGA databases, respectively. A prognostic index (PI) was generated from disease-free survival-associated splicing events (DFS-SEs), which were identified by univariate/multivariate Cox regression analysis. A total of 6,909 DFS-SEs were identified in PRAD. The corresponding genes for the DFS-SEs were significantly enriched in mitochondria and their associated pathways according to Gene Ontology annotation and in the pathways of fatty acid metabolism, oxidative phosphorylation and Huntington's disease according to a Kyoto Encyclopedia of Genes and Genomes pathway analysis. The PI for mutually exclusive exons had the greatest ability to predict the probability of five-year disease-free survival of patients with PRAD, with an area under the time-dependent receiver-operating characteristic curve of 0.7606. Patients with PRAD, when divided into a 'low' and a 'high' group based on their median PI for exon skip values, exhibited a marked difference in disease-free survival (low vs. high, 3,588.45±250.51 vs. 1,531.08±136.50 days; P=7.43×10−9). A correlation network between DFS-SEs of splicing factors and non-splicing factors was constructed to determine the potential mechanisms in PRAD, which included the potential regulatory interaction between the splicing event of splicing factor RNA binding motif protein 5-alternate terminator (AT)-64957 and the splicing event of non-splicing factor heterochromatin protein 1 binding protein 3-AT-939. In conclusion, the PIs derived from DFS-SEs are valuable prognostic factors for patients with PRAD, and the function of splicing events in PRAD deserves further exploration.

The role of collateral related donors in haploidentical hematopoietic stem cell transplantation

A key issue in the haploiedntical hematopoietic stem cell transplantation (haplo-HSCT) setting is the search for the best donor, because donor selection can significantly impact the clinical outcomes. We aimed to identify the role of collateral related donors (CRDs) in donor selection for haplo-HSCT through comparing the clinical outcomes between CRDs (n = 60) and maternal donors (MDs, n = 296), which were the last choice of donor selection in immediate related donors (IRDs). The cumulative incidence of graft-versus-host disease was comparable between CRDs and MDs. The 5-year cumulative incidence of relapse and non-relapse mortality was 22.0% (95% CI, 11.3%–32.7%) versus 17.4% (95% CI, 13.0%–21.8%) (P = 0.455) and 25.0% (95% CI, 13.9%–36.1%) versus 23.1% (95% CI, 18.2%–28.0%) (P = 0.721) for the CRDs and MDs, respectively. The 5-year probabilities of disease-free survival and overall survival was 53.2% (95% CI, 40.4%–66.0%) versus 59.5% (95% CI, 53.8%–65.2%) (P = 0.406) and 56.5% (95% CI, 43.8%–69.2%) versus 61.8% (95% CI, 56.1%–67.5%) (P = 0.458) for the CRDs and MDs, respectively. Female donor/male recipient (FDMR) CRDs were associated with the poorest clinical outcomes, and the clinical outcomes of non-FDMR CRDs were comparable to those of MDs. In summary, our results showed that CRDs did not showed superiority over MDs. Thus, IRDs should be the first choice of donor selection, and CRDs could only be the donors for those without IRDs.

Donor KIR Genotype Impacts on Clinical Outcome after T Cell–Depleted HLA Matched Related Allogeneic Transplantation for High-Risk Pediatric Leukemia Patients

Preliminary data suggest that ex vivo T cell-depleted matched related donor (MRD) hematopoietic stem cell transplantation (HSCT) is feasible and confers a clinically beneficial reduction in graft-versus-host disease. Classically, T cell-depleted grafts were associated with reduction of the graft-versus-leukemia (GVL) effect because of delayed T cell immune reconstitution. However, natural killer (NK) cell alloreactivity is also critical for an early GVL effect as well as for lymphocyte immune reconstitution. Here, we study the role of NK cells in MRD T cell-depleted HSCT, which is still poorly understood. Given that MRD ligands for inhibitory killer cell immunoglobulin-like receptors (KIRs) are matched, we focused on activating KIR receptors. We retrospectively analyzed KIR genotyping in patients and MRDs in 40 ex vivo T cell-depleted pediatric HSCTs. The log-rank test and Cox proportional risk test were performed to correlate genotype with clinical outcome (relapse rate, disease-free survival, and overall survival) and immune reconstitution. The statistical analysis revealed poorer overall survival when donors have a KIR-B content score of ≥2, a best/better subtype, or present the KIR2DS1 gene. The patient's relapse rate was higher when donors present the KIR2DL5A gene, as well as a poorer probability of disease-free survival when the donor is classified with a best/better subtype. Regarding immune reconstitution, donor KIR haplotype A or the presence of inhibitory KIR genes promote best recovery of T lymphocytes, whereas donor KIR haplotype B or the presence of activating KIR genes confer better expansion of NK cells. These findings suggest that the selection of MRDs with an inhibitory KIR phenotype improve T cell expansion as well as the clinical outcome after pediatric ex vivo T cell-depleted HSCT.

Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation

BackgroundMantle cell lymphoma (MCL) is an aggressive and incurable lymphoma. Standard of care for younger patients with MCL is induction chemotherapy followed by autologous stem cell transplantation (auto-HCT). Rituximab maintenance after auto-HCT has been shown to improve progression-free survival (PFS) and overall survival (OS) in MCL. Bortezomib maintenance therapy has also been shown to be tolerable and feasible in this setting. However, the combination of bortezomib and rituximab as maintenance therapy post-auto-HCT has not been studied.MethodsWe conducted a multicenter, phase II trial of bortezomib given in combination with rituximab as maintenance in MCL patients after consolidative auto-HCT. Enrolled patients (n = 23) received bortezomib 1.3 mg/m2 subcutaneously weekly for 4 weeks every 3 months (up to 24 months) and rituximab 375 mg/m2 intravenously weekly for 4 weeks every 6 months (up to 24 months) for a total duration of 2 years. The primary study endpoint was disease-free survival (DFS).ResultsWith a median follow-up of 35.9 months, the 2-year DFS probability was 90.2% (95% CI 66–97), and 2-year OS was 94.7% (95% CI 68–99). The most frequent grade 3/4 toxic events were neutropenia (in 74% of patients) and lymphopenia (in 35%). The incidence of peripheral neuropathy was 48% for grade 1, 9% for grade 2, and 0% for grade 3/4. We also examined the role of quantitative cyclin D1 (CCND1) mRNA in monitoring minimal residual disease.ConclusionCombined bortezomib and rituximab as maintenance therapy in MCL patients following auto-HCT is an active and well-tolerated regimen.Trial registrationClinicalTrials.govNCT01267812, registered Dec 29, 2010.

Yonsei nomogram: A predictive model of new-onset chronic kidney disease after on-clamp partial nephrectomy in patients with T1 renal tumors.

To develop a predictive nomogram for chronic kidney disease-free survival probability in the long term after partial nephrectomy. A retrospective analysis was carried out of 698 patients with T1 renal tumors undergoing partial nephrectomy at a tertiary academic institution. A multivariable Cox regression analysis was carried out based on parameters proven to have an impact on postoperative renal function. Patients with incomplete data, <12 months follow up and preoperative chronic kidney disease stage III or greater were excluded. The study end-points were to identify independent risk factors for new-onset chronic kidney disease development, as well as to construct a predictive model for chronic kidney disease-free survival probability after partial nephrectomy. The median age was 52 years, median tumor size was 2.5 cm and mean warm ischemia time was 28 min. A total of 91 patients (13.1%) developed new-onset chronic kidney disease at a median follow up of 60 months. The chronic kidney disease-free survival rates at 1, 3, 5 and 10 year were 97.1%, 94.4%, 85.3% and 70.6%, respectively. On multivariable Cox regression analysis, age (1.041, P = 0.001), male sex (hazard ratio 1.653, P < 0.001), diabetes mellitus (hazard ratio 1.921, P = 0.046), tumor size (hazard ratio 1.331, P < 0.001) and preoperative estimated glomerular filtration rate (hazard ratio 0.937, P < 0.001) were independent predictors for new-onset chronic kidney disease. The C-index for chronic kidney disease-free survival was 0.853 (95% confidence interval 0.815-0.895). We developed a novel nomogram for predicting the 5-year chronic kidney disease-free survival probability after on-clamp partial nephrectomy. This model might have an important role in partial nephrectomy decision-making and follow-up plan after surgery. External validation of our nomogram in a larger cohort of patients should be considered.

High vascular ligation in left-sided colon cancer surgery is safe and adequate

We aimed to evaluate the safety and adequacy of high vascular ligation in surgery for left-sided colon cancer. Between 2007 and 2016, hand-assisted laparoscopic surgery was performed on 228 patients for descending or sigmoid colon cancer with high ligation of the inferior mesenteric artery and vein. We collected and prospectively studied demographic, clinical, and long-term outcome results. Complications were assessed with the Clavien–Dindo classification. The 5‑year survival (OS) and 5‑year disease-free survival (DFS) probability rates were calculated using Kaplan–Meier curves. There were 71 (31%) patients with stage I disease, 67 (29.7%) with stage II, 65 (28.4%) with stage III, and 25 (10.9%) with stage IV. The average harvested lymph node count was 16.5 ± 10 (range, 10–90). Length of postoperative hospital stay was 6.3 ± 3.2 days (range, 1–30). Eleven (4.82%) patients had complications, and three of them (1.3%) were re-operated. There was no anastomotic leakage detected in our group of patients. The five-year OS of all stages using Kaplan–Meier curves was 0.75 and the DFS was 0.8. Our data support the opinion that high vascular ligation while performing surgery for left-sided colon cancer is safe. Long-term oncological outcomes were similar to those presented in other studies.

Second breast conserving surgery and interstitial radiotherapy for the treatment of breast tumor local recurrences. Five-year results

To report the clinical outcomes of second breast-conserving therapy with perioperative interstitial radiotherapy for the treatment of ipsilateral breast tumor recurrences. Between 1999 and 2015, 33 patients, presenting with an ipsilateral breast tumor recurrence after previous breast conserving therapy, were salvaged by re-excision and perioperative high-dose-rate interstitial brachytherapy. A median of 8 (range: 4-24) catheters were implanted into the tumor bed intraoperatively. A total dose of 22 Gy in 5 fractions of 4.4 Gy was delivered to the tumor bed with a margin of 1-2 cm, on 3 consecutive days. The adjuvant systemic treatments consisted of hormonal therapy for 24 patients (73%) and chemotherapy for 6 patients (18%). The survival results were estimated by the Kaplan-Meier method. Late side effects and cosmetic results were also registered. The median follow-up time following the second breast conserving therapy was 61 months (range: 26-189 months). During the follow-up, 4 patients (12.1%) developed second local recurrence. The five-year actuarial rates of the second local, regional and distant recurrence were 6.3%, 6.1%, and 14.9%, respectively. The five-year probabilities of disease-free, cancer-specific and overall survival were 76.2%, 92.4%, and 89.2%, respectively. Four (12%), 19 (58%), 4 (12%) and 6 (18%) patients had excellent, good, fair and poor cosmetic results, respectively. Grade 2 and 3 fibrosis developed in 9 (27%) and 1 (3%) patients. Asymptomatic fat necrosis was detected in 7 (21%) women. Second breast conserving therapy with perioperative high-dose-rate interstitial brachytherapy is a safe and feasible option for the management of ipsilateral breast tumor recurrences. Interstitial brachytherapy may decrease the risk of second local relapse with acceptable cosmetic results and low rate of late side effects. Hence, in selected cases it can provide a feasible alternative to salvage mastectomy. Orv Hetil. 2018; 159(11): 430-438.

Variables Associated to Pathologic Complete Response, Overall Survival and Disease-Free Survival in the Neoadjuvant Setting for Esophageal Cancer: A Retrospective Cohort Analysis

Objective: The aim of the study was to evaluate prognostic factors during neoadjuvant therapy that can predict pathologic complete response (pCR), overall survival (OS), or disease-free survival (DFS). Summary of background data: Variables that can predict tumor response to neoadjuvant therapy are required for esophageal cancer management. Methods: A retrospective cohort was performed with esophageal cancer patients submitted to neoadjuvant therapy. pCR, OS, and DFS were evaluated. Logistic regression was used to evaluate prognostic factors. This study covered 140 patients, 94 squamous cell carcinomas (SCC), and 44 adenocarcinomas. SCC is more often associated with pCR (compared to adenocarcinoma, OR: 8.07, 95% CI: 2.91–22.38); it has higher probability of DFS (HR for death or recurrence was 0.6, 95% CI: 0.37–0.98); and a higher probability of OS (HR for death was 0.59, 95% CI: 0.35–1). Gender, age, grade of cellular differentiation, chemotherapy regimen, and neoplasm circumferential involvement before neoadjuvant therapy are variables that are unrelated to DFS. Relief of dysphagia, and weight gain were also unrelated to the outcomes. In the multivariate analysis, the weight loss during neoadjuvant therapy was related to higher risk for recurrence or death (HR 1.02, 95% CI: 1–1.04). SCC histologic type was associated with higher probability of pCR, and higher OS and DFS rates. Gender, grade of cellular differentiation, and chemotherapy regimen are variables that are unrelated to pCR, OS, and DFS. Relief of dysphagia and increased levels of albumin after neoadjuvant therapy were also unrelated to the studied outcomes. Weight loss during neoadjuvant chemotherapy was associated with poor DFS rate in the multivariate analysis.

Abstract P3-10-17: Predictors of overall survival and disease-free survival for women diagnosed with invasive breast cancer: A large single-center study

Abstract Background/Objective: Biomarkers such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2neu) are associated with the survival and recurrence of invasive breast cancer (IBC). Presence of these markers often helps to dictate treatment plans. The purpose of this study is to identify the predictors of overall survival (OS) and disease-free survival (DFS) for women diagnosed with IBC. In this study, we compared OS and DSF in the following five categories based on biomarker expression: triple-negative (TN), triple-positive (TP), HER2neu-positive, Luminal A (LA) and Luminal B (LB). Method: We retrospectively examined 6,231 records of women diagnosed with IBC from 2006 through 2015 within the Aurora Health Care system. The majority of the women were white (90.8%) and non-Hispanic (97.4%). The women in this study were categorized in the age groups: 20-39 (4.9%), 40-59 (42.8%), 50-69 (40.7%) and 70+ years (11.6%). We used descriptive statistics for all category and numeric variables. Kaplan-Meier curve was used to compare OS and DFS in the five categories. Cox proportional hazards regression was used to identify the significant predictors of OS and DFS. We used alpha of 0.05 for all statistical tests and all statistical analysis was done using SAS 9.4. Results: OS was 86.39% and the DFS rate was 84.43%. In multivariate analysis significant predictors of OS included age (HR=1.94 for 60-69 vs 20-39 p=0.001 and HR=5.3 for 70+ vs 20-39 p&amp;lt; 0.001), race (HR=0.57, p=0.043 for white vs other), ethnicity (HR=0.34, p=0.032), HER2neu expression (HR=0.58, p &amp;lt;0.001), size of the tumor (HR=1.001 p=0.011), grade differentiation (HR=0.62 p &amp;lt; 0.001) and cancer stages (HR of 1.17, 4.8, 15.2 for II, III and IV vs I, p &amp;lt;0.001). Furthermore treatments such as surgery (HR=0.64, p&amp;lt; 0.001), radiation (HR=0.64, p &amp;lt;0.001), chemotherapy (HR=0.63, p &amp;lt;0.001) and hormonal therapy (HR=0.48, p &amp;lt;0.001) showed significantly improved OS in the patients. Similarly significant predictors of DFS included, age (HR=1.8, p &amp;lt;0.001 for 70+ vs 20-39); PR (HR=0.70, p=0.003), HER2neu (HR=0.60, p &amp;lt;0.001) tumor size (HR=1.001, p=0.002), cancer stage (HR=2.7, 9.2, 25.5 for II, III, IV vs I, p&amp;lt;0.001); differentiation of the tumor (HR=0.75, p=0.002, moderate differentiation; well differentiated, HR=0.50, p &amp;lt;0.001). Moreover, the treatments such as surgery (HR=0.42, p &amp;lt;001) radiation, chemotherapy and hormonal therapy (HR=0.58, 0.62, 0.51 p &amp;lt;0.001) significantly increased DFS. Furthermore OS was better for women diagnosed with TP, LA, HER2, LB types compared to women with TN (p&amp;lt;0.001). Similarly the probability for DFS was higher for TP also was higher compared to the probabilities all the other categories (LA, LB, HER2 and TN p &amp;lt;0.05). LA had better DFS then LB, HER2 and TN. LB and HER2 had better DFS than TN (p&amp;lt;0.05). Conclusion: This large study suggests that treatment based on biomarker expression (ER, PR and HER2/Neu) has improved OS and DFS for women with IBC. Increase in tumor size, cancer stage and poor differentiation of the tumor had adverse effect on both OS and DFS. Treatment modalities such as surgery, radiation, chemotherapy and hormonal therapies significantly improved both OS and DFS. Citation Format: Singh M, Konduri SD, Bobustuc GC, Rovin RA. Predictors of overall survival and disease-free survival for women diagnosed with invasive breast cancer: A large single-center study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-17.

Haploidentical HSCT for hemoglobinopathies: improved outcomes with TCRαβ+/CD19+-depleted grafts

AbstractWe examined outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) using T-cell receptor αβ+ (TCRαβ+)/CD19+-depleted grafts (TCR group, 14 patients) in children with hemoglobinopathies. Patients received a preparative regimen consisting of busulfan, thiotepa, cyclophosphamide, and antithymocyte globulin preceded by fludarabine, hydroxyurea, and azathioprine. The median follow-up among surviving patients was 3.9 years. The 5-year probabilities of overall survival (OS) and disease-free survival (DFS) were 84% and 69%, respectively. The incidence of graft failure was 14%. We compared outcomes to a historical group of 40 patients with hemoglobinopathies who received CD34+-selected grafts (CD34 group). The median follow-up of surviving patients for the CD34 group was 7.5 years. The 5-year probabilities of OS and DFS were 78% and 39%, respectively. The CD34 group had a significantly higher incidence of graft failure (45%) than the TCR group (14%) (P = .048). The incidences of grades 2 to 4 acute graft-versus-host disease (GVHD) in the TCR and CD34 groups were 28% and 29%, respectively, and 21% and 10% (P = .1), respectively, for extensive chronic GVHD. Viral reactivation was common in both groups. The overall incidence of posttransplant lymphoproliferative disorders for the entire group was 16%. Among all patients, 5 developed autoimmune hemolytic anemia or thrombocytopenia, with the overall cumulative incidence of 11%. The 2 groups showed suboptimal CD4+ recovery within the first 6 months of transplantation with no significant difference between groups. These data demonstrate that TCRαβ+/CD19+-depleted grafts are associated with a reduced incidence of graft failure, but delayed immune reconstitution and associated morbidity and mortality remain a significant challenge.

Postoperative hepatic arterial infusion chemotherapy improved survival of pancreatic cancer after radical pancreatectomy: a retrospective study.

ObjectiveTo determine the effect of postoperative hepatic arterial infusion chemotherapy (HAIC) on long-term survival of patients with pancreatic cancer (PC) after radical pancreatectomy.MethodsA total of 87 patients with PC underwent radical pancreatectomy in the First People’s Hospital affiliated to Huzhou Normal College between June 2008 and May 2013. Among these patients, after surgery, 43 received two sessions of HAIC followed by four sessions of systemic chemotherapy (HAIC group), while 44 received six sessions of systemic chemotherapy alone (control group). Both the HAIC and systemic chemotherapy regimen included 5-fluorouracil (1,000 mg/m2) as a 5-h infusion on day 1, and gemcitabine (800 mg/m2) as an over 30-min infusion on days 1 and 8. The toxicity, complication, and long-term survival were retrospectively compared.ResultsNo significant difference in patient characteristics between the two groups was found. No chemotherapy-related deaths were recorded, and no significant difference in toxicities was observed between the two groups. The 5-year disease-free survival probability did not differ between the two groups (P=0.2029, hazard ratio for recurrence=0.7561; 95% CI=0.4768–1.1989, by the log-rank test). The HAIC group had significantly higher 5-year overall survival probability (P=0.0288, hazard ratio for death=0.6059; 95% CI=0.3734–0.9832, by the log-rank test) and higher 5-year hepatic metastases-free survival probability (P=0.0321, hazard ratio for hepatic metastases=0.5006; 95% CI=0.2546–0.9843, by the log-rank test) than the control group.ConclusionsPostoperative HAIC has the potential to prevent hepatic metastases and increase long-term survival probability of patients with PC after radical pancreatectomy.

The Risk of Cancer Might be Lower Than We Think. Alternatives to Lifetime Risk Estimates.

BackgroundEstimates of lifetime cancer risk are commonly used in the clinical setting and in health-care evaluations. These measures are based on lifetime cancer risk estimates and may create an unrealistically frightening perception of cancer risk for an individual. We suggest using two new measures of cancer risk to complement the cancer lifetime risk measure, namely estimates of cancer risk from birth to a specific age or from a specific age to life expectancy.MethodsWe calculated risks using incidence density data from the Israel National Cancer Registry of 2013, applying a well-known formula for calculating risk, for a follow-up time. The joint disease-free survival probability is calculated for several age intervals, and hence the risk (i.e. 1–survival) for the intervals.ResultsThe risk of cancer to age 80 in Jewish men and women, respectively, ranged from about 0.336 and 0.329 at age 0, to 0.279 and 0.237 at age 60. The risk of cancer from birth up to an age in Jewish men and women, respectively, ranged from 0 and 0 at birth to 0.088 and 0.129 at age 60. The risk of cancer to age 80 in Arab men and women, respectively, ranged from 0.298 and 0.235 at age 0 to 0.249 and 0.161 at age 60. The risk of cancer from birth up to an age in Arab men and women, respectively, ranged from 0 and 0 at age 0 to 0.074 and 0.095 at age 60. In Jewish and Arab women, breast cancer risk to age 80 decreased from about 0.127 in Jewish women at age 40 to 0.079 at age 60 and from 0.080 to 0.043 in Arab women; the risk from birth up to a specific age ranged between 0 and 0.056, and 0 and 0.040, respectively.ConclusionThe two proposed new estimates convey important additional information to patients and physicians. These estimates are considerably lower than the frequently quoted 33% lifetime cancer risk and are more relevant to patients and physicians. Similarly, breast cancer risk estimates up to or from a specific age differ considerably from the frequently quoted lifetime risk estimates of 1 in 8 women.

Clinical relevance of DNA methyltransferase 3a (dnmt3a) mutation in patients with acute myeloid leukemia

Background Acute myeloid leukemia (AML) is a complex and heterogeneous hematopoietic tissue neoplasm caused by gene mutations, chromosomal rearrangements, deregulation of gene expression, and epigenetic modifications. DNA methylation is altered in leukemia and can affect cells in three main ways: hypomethylation, hypermethylation, and loss of imprinting. Global hypomethylation has frequently been reported in the blast cells, and it is postulated that this promotes transcription of oncogenes and genes concerned with cell replication. Studies of DNA methylation in AML have revealed a series of subgroups with specific methylation signatures. Patients and methods A total of 45 patients with newly diagnosed AML were included in the study. Moreover, 45 individuals matched for age and sex were selected as controls. Immunophenotyping, conventional cytogenetic analysis, and molecular detection of DNA methyltransferase 3A (DNMT3A) exon 23 mutations were performed. Patient follow-up was performed on day 28 after receiving induction therapy to evaluate the remission status. Results DNMT3A exon 23 mutations were identified in 17.8% of patients with AML. All the mutations were missense and heterozygous. DNMT3A exon 23 mutations were significantly associated with AML with monocytic differentiation (75%) than the wild-type group (27%) (P=0.01). All DNMT3A mutations were observed in patients with intermediate-risk karyotype. There was a statistically significant decrease in the probability of achieving complete remission with shorter overall survival in the mutated group compared with the wild type, whereas no statistically significant difference between both groups in the probability of disease-free survival (P=0.14). Conclusion DNMT3A mutations are associated with poor response to therapy conferring a poor outcome, and seem to add prognostic information in patients with AML harboring it with shorter overall survival. DNMT3A mutations can represent a valuable tool for making therapeutic decisions.

Survival benefit of patients with early-stage ovarian carcinoma treated with paclitaxel chemotherapeutic regimens.

ObjectiveAdjuvant chemotherapy was introduced in patients with early-stage ovarian cancer (OC). The benefit of standard chemotherapeutic regimens including taxane has not been established.MethodsPatients with early-stage OC from the National Health Insurance Research database of Taiwan who received platinum plus cyclophosphamide (CP) or platinum plus paclitaxel (PT) for 3–6 cycles were recruited, and the disease-free survival (DFS) and overall survival (OS) were determined.ResultsA total of 1,510 early-stage OC patients, including 841 who received CP regimen and 699 who received PT regimen, were included. The 2 groups had a similar estimated probability of 5-year DFS (PT vs. CP, 79.0% vs. 77.6%; p=0.410) and OS (84.6% vs. 84.3%; p=0.691). Patients >50 years of age who received the CP regimen had a lower 5-year DFS than the patients ≤50 years of age who received the CP (p<0.001) or PT regimens (p=0.001). Additionally, patients >50 years of age who received the CP regimen had a worse 5-year OS compared with the other 3 groups (p=0.019) (p=0.179 for patients >50 years of age in the PT group; p=0.002 for patients ≤50 years of age in the CP group; and p=0.061 for patients ≤50 years of age in the PT group). Patients with the CP or PT regimen for 3–5 cycles had a similar 5-year DFS and OS compared to 6 cycles (p>0.050).ConclusionChemotherapeutic regimens with taxane could be recommended for early-stage OC patients >50 years of age.

Allogeneic Stem Cell Transplantation versus Tyrosine Kinase Inhibitors Combined with Chemotherapy in Patients with Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Here we compare outcomes between the tyrosine kinase inhibitors (TKIs) plus chemotherapy regimen and allogeneic hematopoietic stem cell transplantation (transplantation cohort) in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) and explore factors associated with prognosis. Data from 145 Ph+ ALL patients were analyzed retrospectively. Patients were treated with imatinib plus chemotherapy and then transplantation or continuous TKIs with chemotherapy based on patient preference. A total of 145 Ph+ ALL patients were recruited for this study (median age, 37 years; range, 14 to 65). Among these patients, 81 were men (55.9%) and 86 underwent IKZF1 detection, which identified 59 patients (68.6%) with IKZF1 deletions. After treatment 136 patients (95.8%) achieved complete remission (CR) eventually. With a median follow-up of 33 months (range, 4 to 114) for CR patients, 77 patients (57.9%) underwent transplantation and 56 (42.1%) received continuous TKIs with chemotherapy. At the 4-year follow-up the cumulative incidence of relapse (CIR), disease-free survival (DFS), and overall survival (OS) were 29.4% (95% confidence interval [CI], 24.9% to 34.4%), 60.9% (95% CI, 56.5% to 65.3%), and 69.2% (95% CI, 65.1% to 73.3%), respectively. Multivariate analysis showed that WBC counts < 30 × 109/L at diagnosis (hazard ratio [HR], 4.2; 95% CI, 1.9 to 9.2; P < .001; HR, 2.6; 95% CI, 1.4 to 4.9; P = .003; HR, 2.7; 95% CI, 1.4 to 5.4; P = .003), 3-log reduction of BCR-ABL levels from baseline after 2 consolidation cycles (HR, 4.4; 95% CI, 1.9 to 9.9; P < .001; HR, 3.1; 95% CI, 1.7 to 5.9; P < .001; HR, 3.5; 95% CI, 1.9 to 8.7; P = .001; defined as “minimal residual disease low level”), and transplantation (HR, 5.0; 95% CI, 2.2 to 11.2; P < .001; HR, 3.3; 95% CI, 1.7 to 6.4; P < .001; HR, 4.1; 95% CI, 1.9 to 8.7; P < .001) were the favorable factors of CIR, DFS, and OS. According to the first 2 risk factors, CR patients were divided into 3 groups: low risk (no factor, n = 42, 31.6%), intermediate risk (1 factor, n = 73, 54.9%), and high risk (2 factors, n = 18, 13.5%). In the low-risk group at the 4-year follow up no significant difference existed between the transplant and nontransplant arms for the probabilities of CIR (8.5% versus 7.7%, P = .671), DFS (88.2% versus 83.9%, P = .426), and OS (96.6% versus 83.3%, P = .128). In the intermediate- and high-risk groups at the 4-year follow-up, CIR (23.6% versus 36.9%, P = .017; 37.5% versus 100.0%, P < .001), DFS (62.4% versus 43.8%, P = .048; 56.2% versus 0%, P < .001), and OS (76.1% versus 47.7%, P = .037; 51.4% versus 6.3%, P = .001) rates were significantly better in the transplant arm than in the nontransplant arm. In surviving patients of the low-risk group, no difference in complete molecular response (CMR) rates (85.7% versus 72.7%, P = .379) between the transplant and nontransplant arms was found. However, in the intermediate-risk group the proportion of CMR was significantly higher in the transplant arm than in the nontransplant arm (82.8% versus 42.9%, P = .006). In the high-risk group 4 of 7 transplant patients (57.1%) were in CMR, and no patients survived in the nontransplant arm. Allogeneic hematopoietic stem cell transplantation confers significant survival advantages for Ph+ ALL patients compared with TKIs plus chemotherapy, especially in intermediate- and high-risk patients.

Outcome Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia Treated with Total Body Irradiation–Free Allogeneic Hematopoietic Stem Cell Transplantation: Comparison of Patients with and Without Central Nervous System Involvement

Hematopoietic stem cell transplantation (HSCT) with a non–total body irradiation (TBI) conditioning regimen has proven feasible for treating patients with acute lymphoblastic leukemia (ALL). However, it is commonly believed that for extramedullary involvement of ALL in sanctuary sites, such as the central nervous system (CNS), TBI shall not be abandoned. In this study, the outcomes of pediatric ALL patients with CNS involvement (CNS+) and without CNS involvement (CNS−) treated with TBI-free allogeneic HSCT were retrospectively compared. The patients received a TBI-free busulfan plus cyclophosphamide conditioning regimen. Comparing CNS+ (n = 27) and CNS− (n = 134) patients, the 5-year probabilities of relapse (44.4% versus 41.8%; P = .799), disease-free survival (DFS; 48.1% versus 43.3%; P = .642) and overall survival (OS; 51.9% versus 47.0%; P = .646) were not significantly different. Although transplantation-related mortality (TRM) was higher in the CNS− patients, the difference between the 2 groups was not significant (3.7% versus 12.7%; P = .177). In multivariate analysis, there were no significant between-group differences in OS (P = .502), DFS (P = .424), relapse rate (P = .226), or TRM (P = .117). These findings suggest that HSCT using a non–TBI-containing conditioning regimen can lead to similar outcomes in pediatric ALL patients with and without CNS involvement. TBI-free allogeneic HSCT might be feasible and effective for CNS+ ALL patients.

Gastrointestinal Cancer

Gastrointestinal Cancer