Advanced Stage Outcomes Research Articles

Number of Retrieved Lymph Nodes during Esophagectomy Affects the Outcome of Stage III Esophageal Cancer in Patients Having Had Pre-Operative Chemo-Radiation Therapy.

Background: Lymphadenectomy plays a crucial role in the surgical management of early- stage esophageal cancer. However, few studies have examined lymphadenectomy outcomes in advanced stages, particularly in patients who initially underwent concurrent chemoradiation therapy. This retrospective study investigates the effect of lymphadenectomy in patients diagnosed with AJCC 8th-edition clinical stage III esophageal squamous cell carcinoma who received concurrent preoperative chemoradiation. Methods: Data from 1994 to 2023 were retrieved from our retrospective database. All patients underwent a uniform evaluation and treatment protocol, including preoperative concurrent chemoradiation therapy comprising cisplatin and 5-fluorouracil, followed by esophagectomy. The analysis encompassed clinical T and N stages, tumor location, tumor grade, pathological T and N stages, pathological stage, and the extent of lymph node dissection. Overall survival, "Free-To-Recurrence", and disease-free survival were assessed via Kaplan-Meier survival curves and the Cox regression model for multivariate analysis. Results: The dataset was stratified into two groups according to extent of lymph node dissection, with one group having <15 dissected nodes and the other having ≥15 dissected nodes. The group with <15 nodes exhibited a shorter "Free-To-Recurrence", worse disease-free survival, and lower overall survival. In multiple-variate analysis (Cox regression model), the number of dissected lymph nodes emerged as a significant factor influencing overall survival and freedom from recurrence. Conclusions: The quantity of lymphadenectomy is a crucial determinant for patients with AJCC 8th-edition clinical stage III esophageal squamous cell carcinoma receiving preoperative concurrent chemoradiation.

Risk factors for 3-year mortality in selected patients with Parkinson's disease from a Romanian cohort.

This study aimed to identify and analyze factors associated with a higher risk of 3-year mortality in patients with Parkinson's disease (PD) within a Romanian cohort, focusing on individuals with more advanced disease stages as indicated by the Hoehn and Yahr scale. We conducted a cross-sectional observational study on 42 patients with PD treated at the Neurology Clinic I, Cluj-Napoca County Emergency Clinical Hospital, between October 2019 and January 2021. All participants were at stages 2.5 or 3 on the Hoehn and Yahr scale at baseline. Various clinical, neuropsychological, and neurophysiological assessments were performed, including evaluations for motor and non-motor symptoms such as anhedonia (via the Snaith-Hamilton Pleasure Scale - SHAPS) and cognitive impairment. The use of antiparkinsonian medications and antidepressants was also recorded. Factors associated with higher mortality risk included a higher anhedonia score (SHAPS > 34; P = 0.03), higher levodopa doses (cutoff = 937.5 mg; P = 0.001), and the administration of mirtazapine (P = 0.04). These findings indicate that non-motor symptoms like anhedonia, along with higher medication doses and specific treatments, play a significant role in influencing mortality risk in advanced PD. This study highlights the multifaceted nature of mortality risk in patients with PD, particularly emphasizing the role of non-motor symptoms and pharmacological treatment. Tailored therapeutic strategies, including closer monitoring of anhedonia and careful management of medication dosages, may be essential in reducing mortality and improving patient outcomes in advanced stages of PD.

Analysis of Serial Neuroblastoma PDX Passages in Mice Allows the Identification of New Mediators of Neuroblastoma Aggressiveness.

Neuroblastoma is a neural crest cell-derived pediatric tumor characterized by high inter- and intra-tumor heterogeneity, and by a poor outcome in advanced stages. Patient-derived xenografts (PDXs) have been shown to be useful models for preserving and expanding original patient biopsies in vivo, and for studying neuroblastoma biology in a more physiological setting. The maintenance of genetic, histologic, and phenotypic characteristics of the original biopsy along serial PDX passages in mice is a major concern regarding this model. Here we analyze consecutive PDX passages in mice, at both transcriptomic and histological levels, in order to identify potential changes or highlight similarities to the primary sample. We studied temporal changes using mRNA and miRNA expression and correlate those with neuroblastoma aggressiveness using patient-derived databases. We observed a shortening of tumor onset and an increase in proliferative potential in the PDXs along serial passages. This behavior correlates with changes in the expression of genes related to cell proliferation and neuronal differentiation, including signaling pathways described as relevant for neuroblastoma malignancy. We also identified new genes and miRNAs that can be used to stratify patients according to survival, and which could be potential new players in neuroblastoma aggressiveness. Our results highlight the usefulness of the PDX neuroblastoma model and reflect phenotypic changes that might be occurring in the mouse environment. These findings could be useful for understanding the progression of tumor aggressiveness in this pathology.

Abstract 5069: Delivering docetaxel and curcumin via a nano-combination-therapy for modulating the progression of neuroblastoma

Abstract Introduction: Neuroblastoma (NB) is a form of extracranial tumor derived from the sympathetic nervous system that affects most often infants and young children. It is a very heterogeneous tumor with different levels of aggressiveness. Despite the multiple therapeutic strategies (i.e. aggressive chemotherapy, surgery, radiotherapy, immunotherapy), the outcome in advanced stages or recurrent diseases is negative. New strategies are needed to improve the therapeutic efficacy of existing drugs and reduce their toxicity. Nanotechnology represents a good tool for reaching this goal. Taken this in mind, the focus of this experimental work was to engineer polymeric biodegradable nanomedicines for co-delivering anti-inflammatory and chemotherapeutic molecules to NB malignant masses. More specifically, the work focused on the synthesis, physico-chemical and biopharmaceutical characterization, in vitro testing and in vivo validation of nanomedicines loaded with the cytotoxic drug Docetaxel (DTXL) and the natural anti-inflammatory compound, Curcumin (CURC). Methods: Four configurations of Spherical Polymeric Nanoparticles (SPNs) - loaded with CURC (CURC-SPNs), loaded with DTXL (DTXL-SPNs), loaded with the combination thereof (CURC/DTXL-SPNs), and empty (SPNs) - were synthesized using an oil-in water emulsion/solvent evaporation technique. SPNs size, zeta potential, and polydispersity index (PDI) were measured by dynamic light scattering. The toxicity of SPNs was determined by an MTT assay on the human NB cell line SH-SY5Y. For in vivo efficacy and biodistribution experiments, homozygous CD1 nu/nu athymic female mice (4 to 6-weeks old) were orthotopically injected with SH-SY5Y cells in the left adrenal gland. Results: Empty, DTXL-SPNs, CURC-SPNs, and CURC/DTXL-SPNs were characterized by a narrow size distribution (PdI &amp;lt; 0.15) with an average hydrodynamic diameter of about 185 nm. All the formulations showed a negative surface ζ-potential, associated with the carboxylate groups in the DSPE-PEG coating. A biphasic release profile was observed for all the 3 formulations, with almost 90% of the total drug mass released within the first 24 hours. In vivo results indicated that mice treated with CURC/DTXL -SPNs had a significant increase in life span as compared to untreated mice (control) (p=0.0002), mice treated with CURC-SPNs (p=0.0205), DTXL-SPNs (p=0.0391), and free DTXL (p=0.0054). Biodistribution experiments showed a 2% ID/g accumulation of the injected dose per tumor mass, regardless of the tumor development stage. This behavior is in agreement with results from a longitudinal Magnetic Resonance Imaging analysis of the malignant masses. Conclusion: The obtained results would suggest that nanomedicines could effectively delivery two therapeutic molecules within the malignant mass and modulate its progression leading to a significant increase in overall survival. Citation Format: Agnese Fragassi, Martina Di Francesco, Fabio Pastorino, Miguel Ferreira, Valentina Di Francesco, Anna Lisa Palange, Christian Celia, Luisa Di Marzio, Michele Cilli, Veronica Bensa, Mirco Ponzoni, Paolo Decuzzi. Delivering docetaxel and curcumin via a nano-combination-therapy for modulating the progression of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5069.

Tre-P-20 - Evaluation of haematopoietic stem cell transplantation in patients diagnosed with cutaneous T cell lymphoma at a tertiary care centre

Tre-P-20 - Evaluation of haematopoietic stem cell transplantation in patients diagnosed with cutaneous T cell lymphoma at a tertiary care centre

Short term outcome of primary un-cemented total hip arthroplasty in osteonecrosis of femoral head

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Osteonecrosis of femoral head (ONFH) is characterised by cell death in the subchondral bone caused by abnormalities of blood flow to the femoral head. About 5% to 13% of arthroplasties are performed yearly for ONFH in United States. Ficat and Arlet classification is the commonest system used for grading of ONFH. Advanced stages 3 and 4 are best managed with total hip arthroplasty (THA). THA restores hip range of movement and allows early ambulation in ONFH.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; After seeking approval from local institutional ethical committee 25 patients with stage 3 and stage 4 ONFH (Ficat and Arlet) were admitted from OPD of SKIMS MC and Hospital Bemina, Srinagar. The study was conducted from February 2018 to February 2020 in department of Orthopaedics SKIMS MC and Hospital Bemina, Srinagar. 25 patients with mean age of 50.64 years comprising of 13 females and 12 males with unilateral osteonecrosis of femoral head with collapsed head underwent uncemented total hip arthroplasty and were followed up to a minimum of 1 year post-operatively.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; Outcome was evaluated by comparing pre-operative and post-operative Harris hip scores. The average Harris hip scores improved from 65.87 in the pre-operative group to 96.54 at 1-year follow-up post-operatively. Marked improvement was noted in pain scores. No revisions were performed during the study. One patient developed superficial surgical site infection which healed with supervised dressings and oral antibiotics.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; Uncemented THA has excellent short-term outcomes in advanced stages of ONFH. It provides mobile hip joint and pain free ambulation shortly after surgery.&lt;/p&gt;

Diagnostic and Prognostic Implications of Cardiac Markers for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HC) is a malignant primary liver cancer which has poor treatment outcomes in advanced stages, and many of the HC patients present with advanced stages. The incidence of death due to HC increase as a result of ineffective treatments for advanced stage disease. Early diagnosis and management has proven benefits in both survival and quality of life. Currently very few biomarkers are available to provide diagnostic and prognostic benefits in HC patients. The present review elaborates the association of cardiac markers in HC disease. The HC disease pathology includes many cardiovascular events like hypoxia and other parameters discussed in this review which have a role in disease advancement, and also may help as diagnostic and / or prognostic markers. The scientific lacuna in association / role of cardiac markers in HC disease is also stated in this review which may be helpful for future research studies and develop cost effective biomarker for early diagnosis of HC.

Gastric Signet Ring Cell Carcinoma: Current Management and Future Challenges.

Recent advances in the epidemiology, pathology, molecular mechanisms, and combined modality therapy (CMT) fields have shown that gastric signet ring cell carcinoma (GSRC) should be considered a distinct cancerous entity. Clinical management of this cancer is challenging, with chemoradioresistance and poor outcomes in advanced stages. Pathological and molecular sets of GSRC demonstrate different features of poor cohesion and differentiation according to the WHO, Japanese Gastric Cancer Association, and Laurén classifications. These features also result in poor response to adjuvant and neoadjuvant chemoradiotherapy. Certain studies of GSRC showed the disputed effectiveness of hyperthermic intraperitoneal chemotherapy and immunotherapy. Our aim was to discuss how an improved understanding of these therapeutic benefits may provide better treatment selection for patients, and therefore improve survival. The challenges in the new understanding of GSRC in routine practice and pathology, and the current limitations of treatment will also be discussed.

Survival in Mycosis Fungoides and Sezary Syndrome: How Can We Predict Outcome?

Early-stage mycosis fungoides (MF) has been associated with long survival. A recent meta-analysis including 6,279 patients with MF and Sezary syndrome found that about 10-20% of stage IB patients don't survive 5 years, whereas patients with advanced-stage MF and Sezary syndrome have a 5-year survival chance of about 20-60%. Identifying prognostic markers to better identify those at risk of limited survival may allow improved management choices and this, coupled with newer treatments, could improve survival.

Genomic Signatures of Immune Activation Predict Outcome in Advanced Stages of Ovarian Cancer and Basal-Like Breast Tumors.

There is an unmet need for new therapies in metastatic ovarian cancer and basal-like breast cancer since no curative therapies are currently available. Immunotherapy has shown to be active in several solid tumors, but particularly more in those where a pre-activated immune state does exist. In this work, we aim to identify biomarkers that could distinguish immune-activated tumors and predict response to therapies in ovarian and basal-like breast cancer, as well as their association with the level of tumor immune infiltration. We found that the combined expression of IFNG, CD30, CXCL13, and PRF1 correlated with better overall survival (OS) in advanced stage ovarian cancer. This was confirmed using an independent dataset from TCGA. Interestingly, we observed that this gene combination also predicted for better prognosis in ovarian tumors with low mutational load, which typically respond less to immunotherapy. Expression of IFNG, CD30, CXCL13, and PRF1 was associated with increased level of immune infiltrates (CD8+ T cells, dendritic cells, and neutrophils) within the tumor. Moreover, we found that these gene signature also correlated with an increased OS and with a higher level of tumor immune infiltrates (B cells, CD8+ T cells, CD4+ T cells, neutrophils, and dendritic cells) in basal-like breast cancer. In conclusion, our analysis identifies genes signatures with potential to recognize immune activated ovarian and basal-like breast cancers with favorable prognosis and with a remarkable predictive capacity in tumors with low mutational burden. The presented results led to a hypothesis being formulated, but prospective clinical studies are needed to support a potential clinical application.

CD44-high neural crest stem-like cells are associated with tumour aggressiveness and poor survival in neuroblastoma tumours.

BackgroundNeuroblastoma is a paediatric tumour originated from sympathoadrenal precursors and characterized by its heterogeneity and poor outcome in advanced stages. Intra-tumoral cellular heterogeneity has emerged as an important feature in neuroblastoma, with a potential major impact on tumour aggressiveness and response to therapy. CD44 is an adhesion protein involved in tumour progression, metastasis and stemness in different cancers; however, there has been controversies about the significance of CD44 expression in neuroblastoma and its relationship with tumour progression.MethodsWe have performed transcriptomic analysis on patient tumour samples studying the outcome of patients with high CD44 expression. Adhesion, invasion and proliferation assays were performed in sorted CD44high neuroblastoma cells. Tumoursphere cultures have been used to enrich in undifferentiated stem-like cells and to asses self-renewal and differentiation potential. We have finally performed in vivo tumorigenic assays on cell line-derived or Patient-derived xenografts.FindingsWe show that high CD44 expression is associated with low survival in high-grade human neuroblastoma, independently of MYCN amplification. CD44 is expressed in a cell population with neural crest stem-like features, and with the capacity to generate multipotent, undifferentiated tumourspheres in culture. These cells are more invasive and proliferative in vitro. CD44 positive cells obtained from tumours are more tumorigenic and metastatic, giving rise to aggressive neuroblastic tumours at high frequency upon transplantation.InterpretationWe describe an unexpected intra-tumoural heterogeneity within cellular entities expressing CD44 in neuroblastoma, and propose that CD44 has a role in neural crest stem-like undifferentiated cells, which can contribute to tumorigenesis and malignancy in this type of cancer.FundingResearch supported by grants from the “Asociación Española contra el Cáncer” (AECC), the Spanish Ministry of Science and Innovation SAF program (SAF2016-80412-P), and the European Research Council (ERC Starting Grant to RP).

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Abstract 1608: Pharmacologic screening identifies synthetic lethality interactions with Chk1 inhibitors in basal-like breast and ovarian cancer

Abstract Basal-like breast cancer and ovarian cancer are considered as unmet entities as patient outcome in advanced stages is short, even receiving the most appropriate treatment. These tumors are characterized by a high grade of genetic instability and a notable impairment of DNA repair processes. Thus, in response to DNA damage, they depend on checkpoint arrest proteins, such as Chek1, to stop division. Inactivation of Chk1 permits cell cycle progression without a proper DNA repair, therefore increasing genetic instability and aneuploidy and eventually leading to cell death. Chk1 inhibitors are currently in clinical development and, therefore, the identification of chemotherapies that could be used as clinical partners to potentiate their effect is a main goal. OVCAR3 and IGROV ovarian cancer cells as well as the basal-like MDA-MB-231 and HS578T cell lines were used to screen for agents that may increase the antiproliferative properties of Chk1 inhibitors. Combination of DNA-damaging agents, like platinum compounds or gemcitabine, with the Chk1 inhibitors LY2603618 and SAR020106 had a synergistic effect, not observed when combined with agents targeting mitosis, like taxotere, eribulin or vinorelbine. A similar antiproliferative effect was observed for PARP inhibitors such as olaparib, reinforcing the concept that inhibition of Chk1 allows cells to enter apoptosis when a relevant genetic instability is present. Clonogenic assays and 3D colony formation studies confirmed the effect observed on proliferation also on invasion and long-term survival. Analyses of cell cycle, cell death and intracellular mediators were performed by flow cytometry and Western blot. The effect of the association of LY2603618 with cisplatin and gemcitabine did not change the cell cycle. However, combination of both agents produced a marked induction of apoptosis. Experiments evaluating caspase activity demonstrated that the principal mechanism associated with the induction of apoptosis was caspase dependent. We also explored combination of agents that have a clear translation to the clinics including double combinations with chemotherapies like cisplatin and gemcitabine. We observed that these triple combinations were more effective than double or single agents. Finally, we wanted to evaluate the antiproliferative effect when adding LY2603618 to olaparib in addition to a DNA-damaging agent. Of note, we observed a higher effect than single-agent olaparib or the chemotherapy. Interestingly, inhibition of Chk1 also reverted the effect of cisplatin in platinum-resistant cells. Our findings support the clinical development of Chk1 inhibitors in combination with DNA-damaging agents in basal-like and ovarian cancer. Citation Format: Eva M. Galan-Moya, Ana Alcaraz-Sanabria, Cristina Nieto-Jimenez, Veronica Corrales-Sanchez, Miriam Nuncia-Cantarero, Juan C. Montero, Atanasio Pandiella, Alberto Ocaña. Pharmacologic screening identifies synthetic lethality interactions with Chk1 inhibitors in basal-like breast and ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1608.

Clinical Outcome of Lateral Wedge Osteotomy of the Radius in Advanced Stages of Kienböck's Disease.

BackgroundRadius osteotomies showed favorable clinical outcome in Kienböck's disease. However, few articles have been published on the long-term outcome of lateral wedge osteotomy of the radius in patients with advanced stage Kienböck's disease.MethodsEleven patients with Lichtman stage IIIB/IV Kienböck's disease (group A; mean follow-up period, 86.1 months; range, 48 to 163 months) and 14 patients with Lichtman stage IIIA Kienböck's disease (group B; mean follow-up period, 85.1 months; range, 49 to 144 months) underwent radial wedge osteotomy between August 2004 and August 2012. Radiological changes of the lunate and radiocarpal joint were compared between two groups after osteotomy. The wrist flexion/extension angle, grip strength, and Disabilities of the Arm, Shoulder and Hand (DASH) scores were evaluated preoperatively and at the final follow-up. The Nakamura Scoring System (NSSK) was used for comprehensive understanding of radiological and clinical outcomes.ResultsNine patients of group A and 11 patients of group B showed radiological improvement in the lunate regarding sclerosis, cystic changes, or fragmentation. No patients showed progression of arthritic changes in radiocarpal and midcarpal joints. The wrist flexion/extension angle, grip strength, and DASH score were significantly improved in both groups after operation, but intergroup difference was not statistically significant at the final follow-up (p = 0.149, p = 0.267, and p = 0.536, respectively). The mean NSSK was 21.6 (range, 15 to 27) in group A and 21.8 (range, 15 to 26) in group B.ConclusionsRadial wedge osteotomy yielded excellent radiological and functional outcomes in advanced stages of Kienböck's disease and these results were comparable to those of Lichtman stage IIIA disease. This technique could be a useful alternative to salvage procedures in the treatment of Lichtman stage IIIB/IV Kienböck's disease without severe radiocarpal arthritis.

Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model.

Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.

The Need for Improvement of the Treatment of Advanced and Metastatic Cervical Cancer, the Rationale for Combined Chemo-Immunotherapy

The prognosis of patients with metastatic cervical cancer is poor with a median survival of 8-13 months. Despite the potency of chemotherapeutic drugs, this treatment is rarely curative and should be considered palliative only. The last decades, targeted therapies such as immunotherapy have emerged as an attractive option for the treatment of these patients. Immunotherapy can consist of different modalities such as monoclonal antibodies, adoptive lymphocyte transfer and vaccines, which all are intended to augment the antitumor immune responses in cancer patients. The available evidence indicates that both active and adoptive immunotherapeutical strategies are quite effective against small tumor burdens, but are usually insufficient to eradicate the disease in patients with advanced stages of different kinds of cancer, despite strong induction of tumor-specific immune responses. Although chemotherapy and immunotherapy have not shown to be curative as single modalities, accumulating evidence suggests that combinations of these treatments hold potential for improved clinical outcomes in advanced stages of cancer. Therefore, the combination of chemotherapy and immunotherapy is no longer considered incompatible, because of the emerging insight that certain chemotherapy-based cancer treatments may activate the immune system against the tumor through several molecular and cellular mechanisms. Chemotherapeutic agents and immunotherapy may thus be synergistic and enhance the clinical response. In this review, we show the rationale for combined chemo-immunotherapeutic strategies, and summarize recent data from clinical trials performed in patients with different types of cancer. Challenges such as the selection of the optimal dose and treatment schedule, will be discussed as well as the identification of immune-specific biomarkers. Furthermore, we evaluated the long-term clinical outcomes of patients with advanced cervical cancer treated with HPV16 E6/E7 SLP vaccination with or without chemotherapy. Finally, the future of vaccination therapy in combination with chemotherapy for the treatment of cervical cancer is discussed.

Improvement in Glycemic Control after Left Ventricular Assist Device Implantation in Advanced Heart Failure Patients with Diabetes Mellitus

Patients with advanced heart failure (HF) often have a co-existing diagnosis of diabetes mellitus. Insulin resistance is an independent risk factor for death in HF patients and is associated with the severity of HF. Left ventricular assist devices (LVAD) have been shown to improve outcomes in advanced stages of HF. In this study we hypothesized that LVAD implantation improves glycemic control in patients with end-stage HF.

High-Dose Therapy and Autologous Stem Cell Transplantation for Extra-Nodal NK/T Lymphoma in Western Patients; A Study From the European Group for Blood and Marrow Transplantation (EBMT).

AbstractAbstract 3148Extra-nodal NK/T lymphoma (ENKTL) is an aggressive malignancy with a unique geographical distribution; rare in Western countries and more frequently encountered in East Asia. ENKTL is invariably associated with Epstein Barr Virus (EBV) and characteristically involves the nasal cavity, though extra-nasal disease is not uncommon. For a majority of patients, treatment outcomes are unsatisfactory. For localised disease, radiotherapy is effective although up to 50% of patients will relapse, usually within a year of first-line therapy. The outcome of advanced stage and relapsed/refractory disease is extremely poor. The role of high-dose therapy and autologous stem cell transplantation (HDT-ASCT) in the treatment algorithm of ENKTL remains unclear. Moreover, there is a paucity of data available on patients undergoing HDT-ASCT for ENKTL outside East Asia.The objective of this study was to analyse the outcome of Western patients with W.H.O-classified ENKTL who had undergone HDT-ASCT from 2000–2009. The European Group for Blood and Marrow Transplantation (EBMT) database identified 102 such patients. Following an invitation to contribute detailed study-specific data, including investigator review of the original histopathology report, a total of 28 patients with full dataset were included for analysis. All patients had a histological diagnosis of ENKTL, with a natural killer (NK) or cytotoxic T cell phenotype in accordance with the W.H.O classification. A majority of biopsies had demonstrable evidence of EBV by EBER or LMP1 staining. For cases where EBV data was not available, cases were only included if a NK or cytotoxic T cell phenotype was demonstrable together with characteristic clinical and radiological features of ENKTL.The median age at ASCT was 47.4 years and the median time from diagnosis to ASCT was 22.4 months. There were no discernible difference in characteristics or outcome between the 28 study patients and the remaining patients recorded on the registry. The median follow-up was 32.8 months post-ASCT.At diagnosis of ENKTL, 57.2% of patients had stage I/II disease. All patients had received at least one line of chemotherapy prior to HDT-ASCT (median 2 lines), whilst only 32.1% had previously received involved-field RT. Remission status at HDT-ASCT was: 43% in first complete remission (CR1); 18% in second or subsequent CR; 21% classified as partial response; and 18% patients with refractory or progressive disease. The 2 year estimates of disease-free survival and overall survival were 40.7% (95%CI: 25.9–64.2) and 52.3% (95%CI: 36.4–75.1) respectively. Disease relapse beyond 12 months was not seen following HDT-ASCT. The 1-year and 2 year non-relapse mortality (NRM) estimates were 11.1% (95%CI 2.7–26.3) and 22.2% (95%CI 8.7 – 39.5) respectively.The 2 year DFS estimate for patients undergoing HDT-ASCT in CR1 was 63.6% (95%CI 40.7–99.5) compared with 25% (10.7–58.4) for patients not in CR1, although this difference did not reach statistical significance (p=0.068). There was no apparent impact of age, stage or number of previous lines of therapy on NRM, DFS or OS. Interestingly, the 2 year DFS and OS for those with stage III/IV disease were 33.3% (95%CI 13.2–84) and 40% (95%CI 18.7–85.5) respectively, with evidence of a survival plateau after 1 year, indicating a proportion of patients with advanced stage ENKTL can be effectively salvaged by HDT-ASCT.This is the largest analysis of HDT-ASCT for patients with WHO-classified ENKTL reported from the Western hemisphere. Survival outcomes are comparable to those reported in East Asian cohorts, although detailed comparison is inherently limited by the nature of the study. Non-relapse mortality is higher than anticipated for a relatively young HDT-ASCT population. Most relapses occurred within 1 year of HDT-ASCT. Outcomes are encouraging for patients with advanced disease. Prospective studies are now urgently required to allow more definitive recommendations to be made on the role of HDT-ASCT for patients with ENKTL. Disclosures:No relevant conflicts of interest to declare.

Results of a phase II study of pralatrexate in patients with advanced/metastatic relapsed transitional cell carcinoma of the urinary bladder.

4574 Background: Antifolate agents have demonstrated activity in transitional cell carcinoma (TCC), a disease with very poor outcomes in advanced stages. Pralatrexate (FOLOTYN, Allos Therapeutics, Inc., Westminster, CO), a folate analogue targeting dihydrofolate reductase, is designed for enhanced uptake and accumulation in tumor cells. The objective of this study was to examine the activity and safety of pralatrexate in patients (pts) with advanced/metastatic TCC of the urinary bladder after failure of prior chemotherapy. Methods: Pts with histologically confirmed TCC (&gt;50% TCC in tumor) received pralatrexate 190 mg/m² intravenously on days 1 and 15 of a 28‑day cycle supplemented with vitamin B12 and folic acid. Included pts had Eastern Cooperative Oncology Group performance status of 0–1, measurable disease, and prior treatment with ≤1 platinum- and/or methotrexate-based regimen in the recurrent/metastatic setting. Results: Thirty pts were enrolled and treated. All pts received prior platinum-based therapy, and 7 pts (23%) received methotrexate in a multidrug regimen. One pt had a confirmed partial response (PR); 4 additional pts had unconfirmed PRs. Twelve pts had stable disease. The median number of cycles received was 2 (range, 1–24), and median time on treatment was 56 days (range, 1–714). The median progression-free survival (PFS) and overall survival for all pts was 4.0 months (95% confidence interval [CI], 2.1–4.5) and 9.3 months (95% CI, 5.6–13.2), respectively. Eight pts (27%) had PFS &gt;6 months and 3 pts (10%) had PFS &gt;12 months. Eight pts (27%) underwent dose reductions, all due to mucositis. Six pts (20%) discontinued the study due to treatment-related adverse events (AEs)—mainly mucositis. The most frequent treatment-related AEs were stomatitis (77%), asthenia (30%), vomiting (27%), and anemia, nausea, and neutropenia (23% each). Conclusions: Pralatrexate showed evidence of activity and durable disease control when used as a single agent in pts with advanced bladder cancer, although the overall response rate was modest. Further study of pralatrexate in this setting should focus on improving drug delivery and evaluation of novel combination approaches.

EPAS1 mRNA in plasma from colorectal cancer patients is associated with poor outcome in advanced stages

The presence of free nucleic acids in plasma has been detected in cancer patients and is associated with poor prognosis. In the present study, the mRNA levels of three genes (EPAS1, KIAA0101 and UBE2D3) in plasma from colorectal cancer patients were analyzed. These genes were selected from a previous study of genomic profiles, discriminating between healthy controls and colorectal cancer patients. mRNA levels were analyzed by real-time PCR in the plasma of 154 patients with colorectal cancer. The association of plasma mRNA levels with clinicopathological parameters and patient survival were analyzed. High levels of EPAS1 in the plasma were associated with patients aged over 50 years, relapse of disease and patient mortality. When patients were divided into two groups, early (I and II) and advanced (III and IV) stages, an association was observed between high levels of EPAS1 mRNA and worse disease-free and overall survival in advanced stages. The expression of KIAA0101 and UBE2D3 was not associated with poor prognosis. Thus, our results suggest that EPAS1 mRNA levels may be an indicator of poor prognosis in colorectal cancer patients at advanced stages, obtained by a non-invasive method.