Higher Disease-free Survival Rate Research Articles

Comparative efficacy of radical prostatectomy and radiotherapy in the treatment of high-risk prostate cancer.

Both radical prostatectomy and radiation therapy are effective in controlling the condition of patients with hormone-resistant prostate cancer (HRPCa). However, there is limited research on the prognosis and quality of life of HRPCa patients after different treatment modalities. To explore the efficacy of radical prostatectomy (RP) and radiotherapy (RT), when treating high-risk prostate cancer (HRPCa). Overall 103 HRPCa patients were included and were divided into RP group and RT group according to different treatment methods. The propensity score matching method (PSM) was used to balance the baseline data of the two groups and match 34 patients in each group. The prognosis, quality of life, and basic efficacy of patients were compared. After intervention, the disease-free survival rate of the RT group was higher than that of the RP group (79.41% vs. 55.88%, p= 0.038). Quality of life scores between the two treatment methods had no difference before intervention (p> 0.05), but higher in RT group than that of the RP group after intervention (p< 0.05). After treatment, there was no statistically significant difference in total effective rate of treatment between two groups (44.12% vs. 58.82%, p> 0.05), but the disease control rate was significantly higher in RT group (94.12% vs. 76.47%, p= 0.040). Radical radiotherapy is effective in the clinical treatment of HRPCa patients, with a higher disease-free survival rate and improved quality of life after treatment, and is worth promoting.

Exploring the Efficacy of Hyperthermic Intraperitoneal Perfusion Chemotherapy in Gastric Cancer: Meta-analysis Based on Randomized Controlled Trials.

Based on randomized clinical trials, this meta-analysis evaluated the efficacy and safety of intent-to-cure or prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of gastric cancer. PubMed, Cochrane Library, Medline, and Embase databases were all systemically searched from 2004 to 2023. The quality of the study was assessed by using the Cochrane risk of bias method. The certainty of the evidence was determined by using the GRADE evaluation. In this study, 12 articles with a total of 1181 patients were analyzed based on the inclusion criteria. The findings revealed that HIPEC had a higher survival rate (risk ratio [RR] 0.60; 95% confidence interval [CI] [0.43, 0.86], P = 0.005, RR 0.82; 95% CI [0.70, 0.97], P = 0.02, RR 0.83; 95% CI [0.71, 0.96], P < 0.01, and RR 0.63 [0.54, 0.73], P < 0.00001) after 1, 2, 3, and 5 years compared with the control group. The RR was statistically significant for 1, 2, 3, and 5 years. Furthermore, the observed overall recurrence rate for the HIPEC group was lower than control group and statistically significant (RR 0.59; 95% CI [0.50, 0.68], P < 0.0001). Higher disease-free survival rate (RR 1.42; 95% CI [1.07, 1.89], P < 0.01) was observed in the HIPEC group and statistically significant. Gastric cancer patients treated with HIPEC have shown promising outcomes with regard to survival, recurrence, disease-free survival, and adverse reactions. However, multicenter trials with larger sample sizes consisting of different ethnicities is suggested.

Comparison of thulium and holmium lasers with conventional transurethral bladder resection for non-muscle invasive bladder cancer

Introduction. The gold standard of treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) is transurethral resection of the bladder (TURB) in combination with intravesical therapy. However, this procedure may cause serious complications. At the same time, studies of various lasers for the treatment of NMIBC have demonstrated their safety and efficacy. Despite this, the topic has not yet been fully explored and is not widely practiced in clinical oncology, making further research necessary.Objective. To compare thulium and holmium lasers with conventional TURB for management of non-muscle-invasive bladder cancer (NMIBC).Materials &amp; methods. In our study, depending on the treatment approach, 84 NMIBC-patients were divided into three groups. Group 1 included 27 patients (34.14%), who underwent laser thulium bladder resection; group 2 included 25 patients (29.76%), who underwent laser holmium bladder resection, and group 3 included 32 patients (38.1%), who underwent standard TURB. Prior to surgery, all patients received a standard set of preoperative general clinical and instrumental examinations for bladder cancer, and the choice of surgical approach was based on informed patient consent, taking into account the benefits and risks of the three treatment options. All surgeries were performed in accordance with established protocols.Results. In the TURB group, the surgery time was the longest and totalled in 20.5 ± 7.4 min. Laser technologies reduce the surgery time to 16.3 ± 5.3 min for a holmium laser and to 14.7 ± 5.2 min for a thulium laser. Also, in groups 1 and 2, a shorter duration of postoperative bladder irrigation was noted (4.4 ± 1.8 and 4.7 ± 1.6 hours) and shorter periods of postoperative bladder catheterisation (1.5 ± 0.08 and 1.6 ± 0.08 days) compared to group 3, where these indicators were 16.4 ± 2.5 hours and 2.5 ± 0.13 days, respectively. Among patients undergoing either holmium or thulium surgery, a higher rate of disease-free survival has been noted. Independent prognostic factors that influence the prognosis of NMIBC in all groups include the type of surgery, history of bladder tumors, and pathological stage.Conclusion. The use of laser technology, such as thulium and holmium laser, in bladder wall resection for NMIBC shows promising results and provides a good clinical outcome that is comparable to (and in some cases, superior to) standard TURB.

The long noncoding RNA MANCR to promote and stabilize triple negative breast cancer.

e13150 Background: Cancer remains a leading cause of death worldwide, despite many advances in cancer treatment over the past decade. Triple Negative Breast Cancer (TNBC) is among the highest with a poor prognosis. Early diagnosis and modern treatment regimens for breast cancer (BC) have led to a high disease-free survival rate. Still, survival decreases significantly for patients with metastatic disease. Long non-coding RNAs are among a recent class of epigenetic regulators that function in the nucleus to support the stability of the cells and maintain the fidelity of chromatin interactions. Our laboratory discovered the long noncoding RNA MANCR (LINC00704) as being upregulated in human BC tumors and this is indicative of a worse survival rate than in patients with low MANCR-expressing tumors. MANCR is aberrantly expressed in TNBC cells, and these cells are highly dependent on MANCR to retain their tumorigenic characteristics. Methods: Our functional in vitro studies in MDA-MB-231 TNBC cells used GapmerRs to knockdown MANCR. For in vivo studies, TNBC cells were injected into the 4th mammary fat pad of mice, allowed initial tumor formation, and then treated the animals with 2 nmol/g of a negative control or MANCR targeting GapmeR. We also identified genome interaction sites at single nucleotide resolution by chromatin isolation by RNA purification (ChIRP)-seq to determine the mechanism of MANCR activity in TNBC cells. Results: We found that MANCR knockdown promotes DNA damage and decreases cell proliferation, migration, anchorage-independent colony formation, transwell invasion, and overall survival. Additionally, targeting MANCR in animals with existing tumors drastically inhibited tumor growth and the end-point tumor mass over time. The MANCR GapmeR treatment also inhibited the ability of TNBC cells to circulate and disseminate to distant organs. After performing ChIRP-seq in the MDA-MB-231 cells, we identified 988 genome-wide binding sites that exhibit MANCR interactions, of which 79% are intergenic and 21% are genic regions. Furthermore, 127 MANCR ChIRP peaks were found to overlap with fragile sites in the genome, indicating MANCR provides stability to these sites. Conclusions: These data suggest that targeting MANCR has therapeutic potential for patients with “MANCR-high” TNBC tumors by disrupting genome stability. Indeed, our in vivo studies demonstrate that “MANCR-high” TNBC tumors require MANCR to rapidly grow and promote disease progression. Lastly, many of the MANCR-chromatin interactions identified were found in intergenic regions and overlap with fragile sites within the genome. Collectively these data strongly indicate that MANCR stabilizes the TNBC genome, and disrupting genome stability by targeting MANCR has therapeutic potential.

Abstract 5151: High serum kidney injury marker-1 and high baseline tumor PD-L1 protein expression levels are independently associated with treatment effect in adjuvant nivolumab plus ipilimumab vs placebo in localized clear cell renal cell carcinoma

Abstract Introduction: CheckMate 914 (CM-914) Part A is a double-blind, phase III randomized trial of the Nivolumab (NIVO) plus Ipilimumab (IPI) vs placebo (PBO) in localized ccRCC. Our prior report from this study suggested a disease-free survival (DFS) benefit for NIVO+IPI among patients with Fuhrman grade 4, TNM stages PT2a and PT4, or sarcomatoid features, although the sample size was limited. It is known that high circulating KIM-1 is associated with worse DFS after nephrectomy. In this exploratory post hoc analysis, we investigated whether high KIM-1 may help identify a subset of patients who benefit from adjuvant NIVO+IPI. Methods: Patients (n=816) with RCC after nephrectomy were randomized in CM-914 Part A to receive NIVO+IPI or PBO as previously described. Assessment of KIM-1 levels was performed using enzyme linked immunoassay (ELISA) on pre-treatment (n=584) and matched on-treatment blood samples (n=584). We used pre-treatment tumor samples to assess PD-L1% tumor cell expression (%TC) in an PD-L1 IHC 28-8 pharm Dx assay. The association between biomarkers and DFS outcomes was investigated by Kaplan-Meier (KM) and Cox proportional hazards analysis. Results: Median baseline serum KIM-1 level was 102 (9.9 - 1055.7) pg/mL. Serum KIM-1 levels were higher in males vs females, ≥65 yrs vs &amp;lt;65 yrs, Asian vs white patients, and patients with partial vs radical nephrectomy. In the PBO arm, subjects with highest quartile of pre-treatment KIM-1 had significantly worse DFS than those from the three lower quartiles. In contrast, this DFS risk among the subjects within the highest KIM-1 quartile was mitigated with NIVO+IPI treatment. Among patients within the highest quartile of pre-treatment KIM-1, there was trend for better DFS for NIVO+IPI versus PBO, HR=0.6 (0.34-1.04). Increase in KIM-1 during study therapy was positively associated with higher DFS rate in both arms. Multivariable analysis showed that PD-L1 %TC was predictive at predefined PD-L1 cutoffs (&amp;gt;=1%, &amp;gt;=5%, and &amp;gt;=10%), associating with improved DFS compared to placebo. Subjects with high PD-L1 expression had a DFS benefit from NIVO+IPI independent of KIM-1. Conclusion: Circulating KIM-1 and tumor PD-L1 expression may enrich for benefit from IO therapy in adjuvant ccRCC and hence holds promise for informing risk stratification and patient inclusion in neoadjuvant or adjuvant clinical trials. Citation Format: Sai Vikram Vemula, Wenxin Xu, Yu Wang, Xiaowen Liu, Jorge Ruiz de Somocurcio, David McDermott, Jun Li, Rupal Bhatt, Chung-Wei Lee, Burcin Simsek, Saurabh Gupta, Robert Motzer. High serum kidney injury marker-1 and high baseline tumor PD-L1 protein expression levels are independently associated with treatment effect in adjuvant nivolumab plus ipilimumab vs placebo in localized clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5151.

Solid pseudopapillary neoplasms of the pancreas: Multicenter Vasepa study

IntroductionSolid pseudopapillary tumors (SPT) of the pancreas are rare exocrine neoplasms of the pancreas. Correct preoperative diagnosis is not always feasible. The treatment of choice is surgical excision. These tumors have a good prognosis with a high disease-free survival rate. ObjectiveTo describe the clinicopathological and radiological characteristics as well as short- and long-term follow-up results of patients who have undergone SPT resection. MethodsMulticenter retrospective observational study in patients with SPT who had undergone surgery from January 2000–January 2022. We have studied preoperative, intraoperative, and postoperative variables as well as the follow-up results (mean 28 months). Results20 patients with histological diagnosis of SPT in the surgical specimen were included. 90% were women; mean age was 33.5 years (13–67); 50% were asymptomatic. CT was the most used diagnostic test (90%). The most frequent location was body-tail (60%). Preoperative biopsy was performed in 13 patients (65%), which was correct in 8 patients. Surgeries performed: 7 distal pancreatectomies, 6 pancreaticoduodenectomies, 4 central pancreatectomies, 2 enucleations, and 1 total pancreatectomy. The R0 rate was 95%. Four patients presented major postoperative complications (Clavien-Dindo > II). Mean tumor size was 81 mm. Only one patient received adjuvant chemotherapy. With a mean follow-up of 28 months, 5-year disease-free survival was 95%. ConclusionSPT are large, usually located in the body-tail of the pancreas, and more frequent in women. The R0 rate obtained in our series is very high (95%). The oncological results are excellent.

Disease-free survival after surgical and combined treatment of newly diagnosed craniopharyngiomas in adults

To clarify disease-free survival in adults with newly diagnosed CP depending on resection quality; to evaluate the effectiveness of stereotactic irradiation and treatment depending on histological characteristics of tumor. We analyzed treatment outcomes in 398 adults over 10-year follow-up. Stereotactic irradiation was performed in 11.6% of patients. The follow-up data were obtained in 68.1% of patients. We compared 5-year disease-free survival rates after different resections with and without subsequent irradiation. Total resection is effective and provides significantly lower risk of CP recurrence. Effectiveness of stereotactic irradiation after incomplete resection was also confirmed. Total resection of ACP and PCP provides high disease-free survival rates. Stereotactic irradiation after incomplete resection is followed by similar outcomes. PCPs are characterized by less aggressive growth and do not recur after total resection.

Effect of intraoperative blood loss on postoperative complications and prognosis of patients with colorectal cancer: A meta‑analysis.

The purpose of the present study was to evaluate whether the amount of intraoperative blood loss (IBL) affects the complications and prognosis of patients with colorectal cancer (CRC). The PubMed, EMBASE and the Cochrane Library databases were used to search for eligible studies from inception to November 30, 2020. Hazard ratios (HRs) and 95% confidence intervals (Cls) were pooled up. The overall survival (OS) and disease-free survival (DFS) were compared between the larger IBL group and the smaller IBL group. The present study was performed with RevMan 5.3 (The Cochrane Collaboration). A total of seven studies involving 1,540 patients with CRC were included in the present study. The smaller IBL group had a higher rate of OS (HR=1.45, 95% CI=1.17 to 1.8, P=0.0007) and a higher rate of DFS (HR=1.76, 95% CI=1.40 to 2.21, P<0.00001). Furthermore, the larger IBL group had a higher rate of postoperative complications than the smaller IBL group (odds ratio=2.06, 95% CI=1.72 to 2.15, P<0.00001). In conclusion, a smaller IBL was associated with better OS and DFS, and a lower risk of postoperative complications compared with a larger IBL in patients with CRC, suggesting that surgeons should pay more attention during perioperative management and surgical operation to reduce IBL.

Preferences of German and Swiss melanoma patients for toxicities versus melanoma recurrence during adjuvant treatment (GERMELATOX-A-trial).

Adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in disease-free survival (DFS). Due to specific side effects, the choice of treatment is very often driven by the risk for toxicity. This study addressed for the first time in a multicenter setting the attitudes and preferences of melanoma patients for adjuvant treatment with (c)ICI and TT. In this study ("GERMELATOX-A"), 136 low-risk melanoma patients from 11 skin cancer centers were asked to rate side effect scenarios typical for each (c)ICI and TT with mild-to-moderate or severe toxicity and melanoma recurrence leading to cancer death. We asked patients about the reduction in melanoma relapse and the survival increase at 5years they would require to tolerate defined side-effects. By VAS, patients on average valued melanoma relapse worse than all scenarios of side-effects during treatment with (c)ICI or TT. In case of severe side effects, patients required a 15% higher rate of DFS at 5years for (c)ICI (80%) compared to TT (65%). For survival, patients required an increase of 5-10% for melanoma survival during (c)ICI (85%/80%) compared to TT (75%). Our study demonstrated a pronounced variation of patient preferences for toxicity and outcomes and a clear preference for TT. As adjuvant melanoma treatment with (c)ICI and TT will be increasingly implemented in earlier stages, precise knowledge of the patient perspective can be helpful for decision making.

Minimising the Toxicities of First Line Hodgkin Lymphoma Treatment in the Modern Era.

Striking advances in the treatment of Hodgkin lymphoma over the last 30 years have culminated in high rates of disease-free survival in younger patients with early and advanced stage disease. In this review we focus on strategies that have evolved over recent years to reduce short and long-term toxicities of treatment. These strategies include the selection of first-line chemotherapy, the stratification of patients based on initial response and subsequent adaptation of treatment, the addition of novel agents (e.g., brentuximab vedotin), the removal of specific drugs (e.g., bleomycin), the use of drug substitution, and the removal of consolidation radiotherapy based on interim and end of treatment PET assessment. While these strategies have successfully reduced toxicity of Hodgkin lymphoma therapy, the cornerstone of treatment continues to be combination chemotherapy and radiotherapy with significant short- and long-term side effects. To further reduce toxicity while maintaining or improving efficacy, we shall need to incorporate novel agents into our first-line treatment algorithms, and several such potentially practice-changing trials are underway.

PARPi treatment enhances radiotherapy-induced ferroptosis and antitumor immune responses via the cGAS signaling pathway in colorectal cancer

In cancer cells, poly (ADP-ribose) polymerase (PARP)-1 and PARP2 initiate and regulate DNA repair pathways to protect against DNA damage and cell death caused by radiotherapy or chemotherapy. Radiotherapy and PARP inhibitors (PARPis) have been combined in clinical trials, but their action mechanisms remain unclear. Here, we show that activated by ionizing radiation (IR) generated dsDNA, cyclic GMP-AMP synthase (cGAS) signaling promoted regulated cell death, specifically ferroptosis, via the activating transcription factor 3 (ATF3)–solute carrier family 7 member 11 axis and the antitumor immune response via the interferon-β-CD8+ T cell pathway. Niraparib, a widely used PARPi, augmented cGAS-mediated ferroptosis and immune activation. In colorectal cancer models, cGAS knockdown (KD) compromised IR-induced ferroptosis via downregulation of ATF3 (key ferroptosis regulator) expression. cGAS depletion reversed IR-induced infiltration of CD8+ T or CD8+GZMB+ T cells in the cGAS KD group. Survival analysis of paired tumor samples before and after standard radiotherapy revealed that high expression levels of cGAS, ATF3, and PTGS2 and high density of CD8+ T cells resulted in a significantly high disease-free survival rate in patients with rectal cancer. Therefore, PARPi treatment increases the cytoplasmic accumulation of dsDNA caused by IR, triggering the cGAS signaling-mediated tumor control in cancer cell lines and mouse xenograft models.

Correlation between Patient-Derived Xenograft Modeling and Prognosis in Osteosarcoma.

ObjectiveTo retrospectively analyze and compare the relationship between the success rate of patient‐derived xenograft (PDX) modeling of osteosarcoma and prognosis (3‐year overall survival rate and disease‐free survival rate) and incidence of lung metastasis.MethodsThe sample group consisted of 57 osteosarcoma patients with definite pathological diagnoses from Shanghai General Hospital from 2015–2017. PDX models in 57 patients were analyzed by retrospective analyses. Among the patients currently inoculated, 20 were tumorigenic in the PDX model, and 37 were nontumorigenic. According to the tumorigenicity of PDXs, the corresponding osteosarcoma patients were divided into two groups. The effects of clinically related indicators on the model were retrospectively compared. The patients were followed, and the 3‐year survival, 3‐year disease‐free survival (DFS), and lung metastasis rates were collected. The relationship between the modeling success and patient prognosis was investigated.ResultsIn the chemotherapy‐treated group, the PDX modeling success rate was 17.4%, and in the nonchemotherapy group, the success rate was 47.1%. The success of PDX modeling was related to whether patients received chemotherapy. The success rate of PDX modeling is significantly reduced after receiving chemotherapy. The 3‐year overall survival rate of the PDX‐grafted group was 49.23%, and that of the PDX‐nongrafted group was 65.71%. There was a significant difference between the two groups, showing a strong negative correlation between the 3‐year survival rate and the success rate of the PDX model. The 3‐year disease‐free survival rate of the PDX‐grafted group was 29.54%. The 3‐year DFS of the PDX‐nongrafted group was 50.34%. There was a significant difference between the two groups. Lower grafted rates indicate a higher DFS rate. The incidence of lung metastasis in the PDX‐grafted group was 32.4%, and that in the nongrafted group was 13.1%. There was a significant difference between the two groups. The successful establishment of the PDX model indicates that patients are more likely to have lung metastases.ConclusionsThe success of PDX modeling often indicates poor prognosis (low 3‐year overall survival rate and disease‐free survival rate) and a greater possibility of lung metastasis. Therefore, PDX modeling in osteosarcoma patients can accurately predict the prognosis of patients and the risk of lung metastasis in advance to help us develop better therapeutic strategies.

Stereotactic radiotherapy (SRT) for differentiated thyroid cancer (DTC) oligometastases: an AIRO (Italian association of radiotherapy and clinical oncology) systematic review.

The aim of this systematic review was to examine efficacy of stereotactic radiotherapy (SRT) in patients with oligometastatic thyroid cancer. A systematic search was conducted by means of PubMed, Scopus, and Cochrane library. gov was searched for ongoing or recently completed trials, and PROSPERO was searched for ongoing or recently completed systematic reviews. We analyzed only clinical studies as full text carried out on patients with oligometastatic thyroid cancer treated with SRT. Conference papers, surveys, letters, editorials, book chapters, and reviews were excluded. Time of publication was restricted to the years 1990-2021. The number of evaluated patients was 146 (267 lesions), and the median age was 58years. The median 1-year local control (LC) was 82% (range 67.0%-97.1%); the median disease-free survival (DFS) was 12months (range 4-53); the median 1-year overall survival was 72% (range 66.6%-85.0%); the 3-year cancer-specific survival was 75.0%; and the 4-year cancer-specific survival was 37.5%. No grade 3-5 acute toxicity was reported. No late effects were recorded. SRT for oligometastases from thyroid cancer as salvage therapy is well tolerated and yields high rates of LC and prolonged DFS.

A Phase II Study of Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Older Patients Using Fludarabine and Total Body Irradiation

Background: Older adults with acute lymphoblastic leukemia (ALL) have poor survival outcomes. Although allogeneic hemaptopoietic stem cell transplantation (allo-hsct) can be curative when used as consolidation after complete remission (CR), advanced age, limited performance status and comorbidities are risk factors for increased non-relapse mortality (NRM) after myeloablative allo-hsct. The 1-year disease-free survival (DFS) for patients ≥40 years who receive an allo-hsct for ALL is often estimated to be 40-50%. Previous studies have demonstrated the efficacy of Total Body Irradiation (TBI) based regimens in adults with ALL when combined with cyclophosphamide (Cy). High-dose Cy is, however, associated with cardiac, hemorrhagic and hepatic toxicities. Fludarabine (Flu) has emerged as a safer substitute of Cy (e.g. Flu/Bu replacing Bu/Cy) with favorable toxicity profile. Given the efficacy of TBI-based regimens in ALL, we hypothesized that a myeloablative regimen of Flu/TBI 12 Gy is almost as effective as Cy/TBI 12 Gy in older adults with ALL undergoing allo-hsct.Methods: We conducted a single center, single-arm phase II clinical trial (NCT01991457) of Flu 40 mg/m 2 IV daily (days -7 to -4) and TBI 2 Gy X2 (days -3 to -1) (12 Gy total) as myeloablative conditioning for older adults (≥40 years old) or younger adults with significant comorbidities with ALL. The primary endpoint of the study was DFS. Secondary endpoints include overall survival (OS), relapse rate, NRM rate and incidence and severity of acute and chronic graft vs. host disease (GVHD). GVHD prophylaxis consisted of Tacrolimus and Methotrexate. Rabbit anti-thymocyte globulin (rATG) was added for unrelated donor type.Results: Nineteen patients were enrolled between October 2013 and February 2019 (Table 1). The median age was 54 years (44-63 years). There were 9 (47%) females and 19 (100%) Non-Hispanic Whites (NHW). The median KPS was 80 (70-100) and 3 (16%) patients had an HCT-CI of ≥3.Seven (37%) patients had Ph-negative B-cell ALL, 9 (47%) had Ph-positive B-cell ALL and 3 (16%) had lymphoid blast phase of chronic myeloid leukemia (CML-LBP). All patients were in CR1 at the time of transplant. Twelve (63%) patients had an 8/8 matched unrelated donor (MUD) and 7 (37%) had a matched related donor (MRD). The median time to neutrophil engraftment was 12 days (10-24 days). Day 100 post-transplant grades III-IV non-hematological and non-infectious adverse effects included mucositis (16%), acute kidney injury (16%), cardiovascular (11%) and elevated liver enzymes (5%).The cumulative incidence (CI) of grades II-IV and III-IV aGVHD at day 100 post-transplant was 26.1% (95% CI 19.3%-39.2%) and 16.2% (95% CI 12.4%-31.3%), respectively. The 2-year CI of mild, moderate and severe cGVHD was 5.0% (95% CI 2.1%-12.3%), 11.3% (95% CI 7.4%-33.3%) and 21.1% (95% CI 13.5%-40.3%), respectively (Table 2). There were 4 cases of cGVHD of the lungs (3=severe, 1=moderate). Other organs involved included skin (n=5), oral (n=5) and ocular (n=4).The CI of relapse and NRM at 2-years was 7.1% (95% CI 5.4%-20.7%) and 31.4% (95% CI 19.4%-50.1%), respectively (Figure 1). The 2-year DFS and OS rates were 63.2% and 68.4%, respectively (Figure 2a and 2b). The median OS was 40 months (95% CI 8.5-71.5).Conclusion: Flu/TBI (12 Gy) resulted in low incidence of relapse with a high DFS and OS rate in an older population with ALL. Increased incidence of severe cGVHD of the lungs was observed with this regimen. Further investigation into this regimen, as a myeloablative regimen for older patients with ALL, is warranted. [Display omitted] DisclosuresDi Stasi: University of Alabama at Birmingham: Current Employment; Syndax Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees. Saad: Incyte Pharmaceuticals: Consultancy; careDx: Consultancy; Amgen: Research Funding; Kadmon: Research Funding; OrcaBio: Research Funding; Magenta Therapeutics: Consultancy.

Clinical Significance of Mitochondrial DNA Content in Acute Promyelocytic Leukemia

Used in the clinical practice for more than three decades, the all-trans retinoic acid (ATRA) rendered acute promyelocytic leukemia (APL) the most curable subtype of acute myeloid leukemia, and currently, its combination with arsenic trioxide (ATO) exceeded all expectations for a chemotherapy-free protocol. In terms of metabolic importance, ATRA can also modulate the mitochondria-mediated cellular metabolism and promote a shift from a glycolytic-driven metabolism to an oxidative phosphorylation profile, although this effect has never been demonstrated in APL. As part of the cellular metabolic machinery, mitochondrial DNA (mtDNA) content has been reported to be altered in different types of solid tumors with clinical implication on patient treatment outcomes, although its clinical significance in acute leukemias has not been investigated to the same extent. Particularly in acute promyelocytic leukemia (APL), the role of mtDNA content on prognostication is completely unknown. Considering that mostly APL samples display a glycolytic-driven metabolism, it is conceivable that APL patients harboring high mtDNA content may present a better response to ATRA-based therapies. To test this hypothesis, we determined the mtDNA content in samples from patients with APL enrolled in the International Consortium on Acute Promyelocytic Leukemia study (Rego et al. Blood. 2013 Mar 14;121(11):1935-43) and analyzed its relationship to treatment outcomes. Diagnostic bone marrow (BM) mononuclear cells from 156 consecutive patients with APL (median age: 35 years, range: 18-82 years; 45% male) were obtained at diagnosis. For comparison purposes, we also included peripheral blood (PB) from 293 age- and sex-adjusted healthy volunteers. First, we determined whether mtDNA content could be compared between PB mononuclear cells and BM. To do so, we measured the mtDNA content of 22 APL patients, for whom paired samples were available at the time of diagnosis and detected a strong correlation between PB and BM samples (Pearson correlation coefficient, r=0.78, 95% confidence interval, CI: 0.54 to 0.9). Next, we used the values of mtDNA higher than the 95 th percentile of healthy subjects (≥1.63. Note: this value represents a fold change relative to healthy control) to define APL patients with high mtDNA content. Patients that presented values within the range of normal control samples (<1.63) were classified as normal mtDNA content. The median follow-up among survivals was 40 months (95%CI: 34-47 months). Of the 131/156 patients who achieved complete remission, 18 patients (14%) relapsed. mtDNA content had no impact on complete remission achievement (84% for normal mtDNA versus 83% for high mtDNA; P=0.924) or overall survival (78% for normal mtDNA versus 80% for high mtDNA; P=0.69). In contrast, patients with high mtDNA content had a significantly high 5-year disease-free survival rate (86%, 95%CI: 78-95%) than patients with normal mtDNA content (61%, 95%CI: 46-82%). Considering non-relapse death as a competing cause of failure, the 5-year cumulative incidence of relapse (CIR) for patients with high and normal mtDNA content were 35% (95%CI: 16-49%) and 10% (95%CI: 2-17%), respectively. The multivariate Cox proportional hazards model showed that mtDNA content was independently associated with CIR (hazard ratio, HR: 0.31, 95%CI: 0.12-0.8) considering PETHEMA/GIMEMA risk of relapse subgroups and age as confounders. To functionally evaluate the metabolic alterations in APL cells upon ATRA treatment, NB4 cell line was treated with ATRA (1 µM) for 48 and 72 hours. In vitro analyses demonstrated (as expected) that the treatment with resulted in increased levels of myeloid maturation markers (CD11b/CD11c/CD15), with morphological changes being only observed at 72 hours. Metabolically, we observed an increase in mitochondrial mass and potential upon ATRA-treatment after 48 hours, which was also reflected by increase in the mtDNA content (2-fold increase in comparison with the vehicle). Together, these findings demonstrate an important, but not completely understood role for mtDNA content in APL. DisclosuresSilveira: BMS/Celgene: Research Funding; Servier/Agios: Research Funding; Abbvie: Speakers Bureau; Astellas: Speakers Bureau. Pagnano: EMS: Other: Lecture; Jansenn: Other: Lecture; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pintpharma: Other: Lecture.

Molecular-Genetic Portrait of Breast Cancer with Triple Negative Phenotype.

Simple SummaryBreast cancer is a genetically heterogeneous disease with different molecular biological and clinical characteristics. The available knowledge about the genetic heterogeneity of the most aggressive molecular subtype of breast cancer—triple-negative—has led to discoveries in drug treatment. Identification of the molecular-genetic phenotype of breast cancer is an important prognostic factor of the disease and allows personalization of the patient’s treatment.Understanding of the genetic mechanisms and identification of the biological markers of tumor progression that form the individual molecular phenotype of transformed cells can characterize the degree of tumor malignancy, the ability to metastasize, the hormonal sensitivity, and the effectiveness of chemotherapy, etc. Breast cancer (BC) is a genetically heterogeneous disease with different molecular biological and clinical characteristics. The available knowledge about the genetic heterogeneity of the most aggressive molecular subtype of breast cancer—triple-negative (TN)—has led to discoveries in drug treatment, including the use of DNA damaging agents (platinum and PARP inhibitors) for these tumors, as well as the use of immunotherapy. Most importantly, the ability to prescribe optimal drug treatment regimens for patients with TNBC based on knowledge of the molecular-genetic characteristics of this subtype of BC will allow the achievement of high rates of overall and disease-free survival. Thus, identification of the molecular-genetic phenotype of breast cancer is an important prognostic factor of the disease and allows personalization of the patient’s treatment.

Arsenic trioxide dose capping to decrease toxicity in the treatment of acute promyelocytic leukemia.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

Role of eIF3C Overexpression in Predicting Prognosis of Intrahepatic Cholangiocarcinoma.

Elevated expression of eukaryotic initiation factor 3c (eIF3C) was recently uncovered to promote several types of cancer progression by inducing cell proliferation. Here, we aimed to assess the expression and prognostic value of eIF3C in intrahepatic cholangiocarcinoma (ICC) patients. Expression of eIF3C was analyzed by immunohistochemistry in tissue microarrays (TMAs) containing 138 ICC and paired peritumoral tissues from ICC patients. Then, the roles of eIF3C in ICC cells were investigated by RNA interference, and the relationship between the eIF3C and KI67 expression was explored in ICC cells and tissues. Finally, the relation between the eIF3C level and clinicopathologic features of ICC was probed, and Kaplan-Meier and Cox's analyses were performed to assess the prognostic merit of eIF3C and KI67 in ICC patients. The expression of eIF3C was elevated in ICC tissues compared to paired peritumoral tissues, which was consistent with the result from the GEPIA database. The downregulation of eIF3C in ICC cells impaired the cellular invasion, metastasis, colony formation, and proliferation. Moreover, we further found a positive relationship between the eIF3C and KI67 expression in ICC cells and tissues. The expression of eIF3C in ICC tissues was positively correlated with lymphatic metastasis (p = 0.049), and the high level of KI67 was frequently found in ICC patients with the large tumor (p = 0.028), high serum AFP (p = 0.019), or lymphatic metastasis (p = 0.039). Notably, patients with the eIF3C or KI67 overexpression had shorter overall survival and higher disease-free survival rates than those with low expression of eIF3C or KI67, and the combination of eIF3C or KI67 expression was an independent parameter for predicting the prognosis and recurrence of ICC patients. Elevated eIF3C expression promotes ICC development, and combination of eIF3C and KI67 is a valuable predictor of the survival and recurrence of ICC patient.

Effectiveness of Sequential Chemoradiation vs Concurrent Chemoradiation or Radiation Alone in Adjuvant Treatment After Hysterectomy for Cervical Cancer

There is no current consensus on the role of chemotherapy in addition to radiation for postoperative adjuvant treatment of patients with early-stage cervical cancer with adverse pathological factors. To evaluate the clinical benefits of sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT) compared with radiation alone (RT) as a postoperative adjuvant treatment in early-stage cervical cancer. After radical hysterectomy at 1 of 8 participating hospitals in China, patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB to IIA cervical cancer with adverse pathological factors were randomized 1:1:1 to receive adjuvant RT, CCRT, or SCRT. Data were collected from February 2008 to December 2018. Patients received adjuvant RT (total dose, 45-50 Gy), CCRT (weekly cisplatin, 30-40 mg/m2), or SCRT (cisplatin, 60-75 mg/m2, plus paclitaxel, 135-175 mg/m2) in a 21-day cycle, given 2 cycles before and 2 cycles after radiotherapy, respectively. The primary end point was the rate of disease-free survival (DFS) at 3 years. A total of 1048 women (median [range] age, 48 [23-65] years) were included in the analysis (350 in the RT group, 345 in the CCRT group, and 353 in the SCRT group). Baseline demographic and disease characteristics were balanced among the treatment groups except that the rate of lymph node involvement was lowest in the RT group (18.3%). In the intention-to-treat population, SCRT was associated with a higher rate of DFS than RT (3-year rate, 90.0% vs 82.0%; hazard ratio [HR], 0.52; 95% CI, 0.35-0.76) and CCRT (90.0% vs 85.0%; HR, 0.65; 95% CI, 0.44-0.96). Treatment with SCRT also decreased cancer death risk compared with RT (5-year rate, 92.0% vs 88.0%; HR, 0.58; 95% CI, 0.35-0.95) after adjustment for lymph node involvement. However, neither DFS nor cancer death risk was different among patients treated with CCRT or RT. In this randomized clinical trial, conducted in a postoperative adjuvant treatment setting, SCRT, rather than CCRT, resulted in a higher DFS and lower risk of cancer death than RT among women with early-stage cervical cancer. ClinicalTrials.gov Identifier: NCT00806117.

Update on systemic treatment in early triple negative breast cancer.

Triple negative breast cancer (TNBC) is a heterogeneous disease representing about 15% of all breast cancers. TNBC are usually high-grade histological tumors, and are generally more aggressive and difficult to treat due to the lack of targeted therapies available, and chemotherapy remains the standard treatment. There is a close relationship between pathological complete response after chemotherapy treatment and higher rates of disease-free survival and overall survival. In this review of systemic treatment in early triple negative breast cancer, our purpose is to analyze and compare different therapies, as well as to highlight the novelties of treatment in this breast cancer subtype.