Toxicity Of Chemotherapy Regimen Research Articles

Prevention of febrile neutropenia in oncological patients: real-world data

Aim. To assess the effect of febrile neutropenia (FN) prophylaxis with granulocyte colony-stimulating factors (G-CSF) in real-world cancer patients.
 Materials and methods. We conducted a statistical analysis of anonymized medical records collected in the Webiomed platform. Before analysis, the cards were validated by clinical experts. Electronic records were extracted according to two principles: mentioning D70 in the diagnosis or mentioning a chemotherapy regimen associated with a high risk of FN (20%), requiring the primary prevention of neutropenia. Thus, we obtained two datasets comprising 47.085 (590 patients) and 30.523 (398 patients) records, respectively.
 Results. Based on the analysis results, the most common risk factors for FN development were highly hematologically toxic chemotherapy regimens and elderly age about 50% in the adult population. In both datasets, the number of female patients prevailed (63.7% in dataset 1, 91.2% in dataset 2), so the most common was breast cancer. Less common were cervical cancer, digestive cancer, and lung cancer. Despite the indications for primary prevention of FN, for safety and importance of achieving the planned dose intensity, it was administered in 18.3% of patients in dataset 1 and 2.3% in dataset 2. No FN or G-CSF-related adverse events were reported in patients who received adequate primary prevention.
 Conclusion. Some issues related to G-CSF administration in cancer patients were identified. We identified the insufficient provision of patients with primary prevention of FN, which negatively affects survival rates and reduces adherence to antitumor therapy. Real-world data demonstrate the efficacy and safety of FN prevention and planned dose intensity maintance in cytotoxic therapy regimens.

A Transcriptomic-Based Tool to Predict Gemcitabine Sensitivity in Advanced Pancreatic Adenocarcinoma

A Transcriptomic-Based Tool to Predict Gemcitabine Sensitivity in Advanced Pancreatic Adenocarcinoma

Molecular Landscape in Infant High-Grade Gliomas: A Single Center Experience.

High-grade gliomas (HGG) represent about 15% of all pediatric brain tumors, with a dismal prognosis and survival rates ranging from 15 to 35%. Approximately 10–12% of pediatric HGGs (pHGG) occur in children younger than five years of age at diagnosis, specifically infants (iHGG), with an unexpected overall survival rate (OS) in 60–70% of cases. In the literature, iHGGs include a large variety of heterogeneous lesions with different molecular profiles that likely explain their different outcomes. We report our single-institution experience of iHGG including 11 children under five years of age with newly diagnosed HGG between 2011 and 2021. All patients received surgery and adjuvant chemotherapy; only two patients received radiotherapy because their age at diagnosis was more than four years-old. Molecular investigations, including next generation sequencing (NGS) and DNA methylation, detected three NTRK-fusions, one ROS1-fusions, one MN1-rearrangement, and two PATZ1-fusions. According to the molecular results, when chemotherapy failed to control the disease, two patients benefited from target therapy with a NTRK-Inhibitor larotrectinib, achieving a complete remission and a very good partial response, respectively, and no severe side-effects. In conclusion, molecular investigations play a fundamental role in the diagnostic work-up and also in the therapeutic decision. Their routine use in clinical practice could help to replace highly toxic chemotherapy regimens with a target therapy that has moderate adverse effects, even in long-term follow-up.

O-P04 Sonodynamic Therapy Complements PD-L1 Immune Checkpoint Inhibition in a Murine Model of Pancreatic Cancer

Abstract Background The emergence of immune checkpoint inhibitors (ICI’s) in the past decade has proven transformative in the area of immuno-oncology. The PD-1 / PD-L1 axis has been particularly well studied and monoclonal antibodies developed to block either the receptor (anti PD-1) or its associated ligand (anti PD-L1) can generate potent anti-tumour immunity in certain tumour models. However, many “immune cold” tumours remain unresponsive to ICI’s. Sonodynamic therapy (SDT) is a targeted anti-cancer treatment that uses ultrasound to activate a sensitiser with the resulting generation of reactive oxygen species (ROS) causing direct cell death. SDT has also been shown to stimulate the adaptive immune system in a pre-clinical cancer model. We investigate the ability of combining ICI and microbubble mediated SDT at controlling tumour growth in a bilateral pancreatic cancer model. Methods Preparation of O2MB-RB are shown below (scheme 1). Cytotoxicity of SDT and immunotherapy in-vivo are illustrated below (Figure 1). Figure 1 highlights that T110299 cells were subcutaneously implanted in the right and left dorsum of C57 mice. Group 1 received an IP injection of anti-mouse PD-L1 antibody (10mg/kg). After 2 hours, mice in this group received an IV injection of O2MB-RB suspension while receiving ultrasound applied to the right-hand-side (target) tumour. Group 2 received the same as Group 1 but no anti PD-L1 antibody; Group 3 received anti-PD-L1 antibody alone and Group 4 remained untreated. Flow cytometry analysis were carried out to investigate tumour infiltrating CD4+ and CD8+ T-lymphocytes. Results The results demonstrated a significant 287% decrease in tumour volume when compared to untreated animals 11 days following the initial treatment with SDT, which reduced further to 369% when SDT was combined with anti-PD-L1 ICI treatment. Analysis of residual tumour tissues remaining after treatment revealed increased levels of infiltrating CD4+ and CD8+ T-lymphocytes (respectively 4.65 and 3.16-fold more) in the off-target tumours of animals where the target tumour was treated with SDT and anti-PD-L1, when compared to untreated tumours. These results suggest that SDT treatment elicits an adaptive immune response that is potentiated by the anti-PD-L1 ICI in this particular model of pancreatic cancer. Conclusions In conclusion, microbubble mediated SDT treatment of a target tumour in a bilateral tumour model of pancreatic cancer, enables growth control at both the target and off-target tumours which is further enhanced when combined with anti-PD-L1 ICI treatment. Combining SDT with anti-PD-L1 ICI treatment, which is also well tolerated, could provide an attractive treatment option for pancreatic cancer, particularly for patients with advanced disease who may not be physically capable of undertaking a toxic chemotherapy regimen.

Review of Treatment Options for the Management of Advanced Stage Hodgkin Lymphoma.

Simple SummaryThe cure rate of Hodgkin lymphoma is currently higher than 80% for almost all stages at diagnosis. Despite the particularly good efficacy of chemotherapy and radiotherapy, some late complications such as cardiovascular disease and second malignancies can occur in a small proportion of patients. A major concern nowadays is, therefore, to find the balance between remission and toxicity in the development of new treatments for classical Hodgkin lymphoma. This review focuses on how to best treat first-line advanced Hodgkin lymphomas, considering the acute and long-term consequences of chemotherapy and radiotherapy treatments. New drugs such as brentuximab vedotin and checkpoint inhibitors are also a field of interest.Hodgkin lymphoma (HL) is a lymphoid-type hematologic disease that is derived from B cells. The incidence of this lymphoid malignancy is around 2–3/100,000/year in the western world. Long-term remission rates are linked to a risk-adapted approach, which allows remission rates higher than 80%. The first-line treatment for advanced stage classical HL (cHL) widely used today is doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) chemotherapy. Randomized studies comparing these two regimens and a recently performed meta-analysis have demonstrated consistently better disease control with BEACOPPesc. However, this treatment is not the standard of care, as there is an excess of acute hematological toxicities and therapy-related myeloid neoplasms. Moreover, there is a recurrent controversy concerning the impact on overall survival with this regimen. More recently, new drugs such as brentuximab vedotin and checkpoint inhibitors have become available and have been evaluated in combination with doxorubicin, vinblastine, and dacarbazine (AVD) for the first-line treatment of patients with advanced cHL with the objective of tumor control improvement. There are still major debates with respect to first-line treatment of advanced cHL. The use of positron emission tomography-adapted strategies has allowed a reduction in the toxicity of chemotherapy regimens. Incorporation of new drugs into the treatment algorithms requires confirmation.

Abstract 1789: Repurposing the anti-depressant sertraline to target serine/glycine synthesis addicted cancer

Abstract Metabolic reprogramming is a well-established hallmark of cancer cells, which supports tumor growth, survival, and chemotherapy resistance. In this respect, a subset of cancers gets addicted to intracellular serine/glycine synthesis via overexpression of the enzymes PHGDH, PSAT1, PSPH or SHMT1/2. This cancer-specific dependency highlights a novel therapeutic opportunity, as normal cells solely rely on serine and glycine uptake from their environment. Well established examples of serine/glycine-synthesis addicted tumors are triple-negative breast cancer and T-cell leukemia (1, 2), which are both currently treated with toxic intensive chemotherapy regimens. In the past decade, researchers have attempted to repurpose approved drugs for cancer treatment, with the aim to develop less toxic low cost therapies that can rapidly enter the clinical practice. In this work, we made use of Candida albicans biofilms as a lower eukaryotic screening system that specifically upregulates expression of serine/glycine synthesis enzymes in response to sub-lethal stress. Using this platform, we discovered two repurposed compounds, sertraline and thimerosal, that show selective toxicity to serine/glycine synthesis dependent cancer cell lines, while they had no effect on cancer and normal lymphoid cell lines that take up serine and glycine from their environment. By using a combination of a PHGDH enzymatic activity assay, molecular docking and labeled serine tracing experiments, we discovered that sertraline and thimerosal inhibit serine/glycine synthesis enzymes SHMT and PHGDH respectively. In contrast to thimerosal, for which clinical applications are limited because of a toxic mercury group in its structure, sertraline is a widely used anti-depressant for which synergy with established anticancer drugs in breast cancer had already been described. Most notably, combining sertraline with a mitochondrial inhibitor, such as the clinically used antimalarial drug artemether, resulted in an even more pronounced inhibition of serine/glycine synthesis dependent proliferation, both in cultured cells and in an in vivo breast cancer xenograft model. Collectively, our study provides molecular insights into the repurposed mode-of-action of sertraline and allows to delineate a hitherto unidentified group of cancers that are particularly sensitive to treatment with sertraline, including breast cancers and leukemias.

The effect of chemotherapy on olfactory function and mucociliary clearance.

Olfactory sensory neurons and the olfactory mucosa are both important for optimal olfactory function. The potential nasal mucosal toxicity of chemotherapy regimens has not been assessed yet. The aim of this study was to objectively investigate the effect of chemotherapy on mucociliary clearance and olfactory function and to evaluate whether this effect differs between different chemotherapy regimens and age groups. The study included consecutive patients admitted for the treatment of a variety of primary tumors (except head and neck and brain malignancies). Patients were evaluated for olfaction and mucociliary clearance before and immediately after completing the last session of chemotherapy cycles, according to the therapeutic protocol. For objective evaluation, the saccharine test was used for mucociliary clearance and the Sniffin' Sticks test for olfactory function. Of the 46 initial patients, 30 completed the study. Groups were formed according to the chemotherapy regimen (four groups: CA (doxorubicin + cyclophosphamide), Folfox (oxaliplatin +5-FU + folinic acid), DCF (docetaxel + cisplatin +5-FU), and GC (gemcitabine + cisplatin)) and according to age (two groups: < 55 years and > 55 years). In the overall analyses, significant deterioration was noted in both mucociliary clearance time and smell scores (olfactory threshold (OT), olfactory discrimination (OD), olfactory identification (OI), and the composite threshold-discrimination-identification (TDI) score). The changes in these scores showed no significant differences between chemotherapy groups. The decrease in OT and global TDI scores was more severe in the younger age group. Chemotherapy impairs both the mucociliary clearance and olfactory function in cancer patients. This might reflect the collective negative effect of chemotherapy on olfactory function, not only through the neurocytotoxic effect but also the cytotoxic effect on the nasal mucosa. In addition, the reduction in olfactory threshold and total olfactory function scores was seen to be more profound in younger patients, which could have been due to higher initial scores.

Chemotherapy accelerates immune-senescence and functional impairments of V\u03b42pos T cells in elderly patients affected by liver metastatic colorectal cancer

Human (gamma delta) γδ T cells are unconventional innate-like lymphocytes displaying a broad array of anti-tumor activities with promising perspectives in cancer immunotherapy. In this context, Vδ2pos T cells represent the preferential target of several immunotherapy protocols against solid tumors. However, the impact of both aging and chemotherapy (CHT) on Vδ2pos T cells is still unknown. The present study evaluates with multi-parametric flow cytometry the frequencies, terminal differentiation, senescence and effector-functions of peripheral blood and tumor infiltrating Vδ2pos T cells purified from liver metastases (CLM) of patients affected by colorectal cancer (CRC) compared to those of sex- and age-matched healthy donors. The peripheral blood of CLM patients underwent CHT is characterized by decreased amounts of Vδ2pos T cells showing a relative increase of terminally-differentiated CD27neg/CD45RApos (TEMRA) cells. The enrichment of this latter subset is associated with an increased expression of the senescent marker CD57. The acquisition of CD57 on TEMRA Vδ2pos T cells is also coupled with impairments in cytotoxicity and production of TNF-α and IFN-γ. These features resemble the acquisition of an immune-senescent profile by Vδ2pos T cells from CLM patients that received CHT, a phenomenon that is also associated with the loss of the co-stimulatory marker CD28 and with the induced expression of CD16. The group of CLM patients underwent CHT and older than 60 years old showed higher frequencies of CD57pos and TEMRA Vδ2pos T cells. Similar results were found for tumor infiltrating Vδ2pos T cell subset purified from CLM specimens of patients treated with CHT. The toxicity of CHT regimens also affects the homeostasis of Vδ2pos T cells by inducing higher frequencies of circulating CD57pos TEMRA subset in CLM underwent CHT and younger than 60 years old. Taken together, our data demonstrate that the enrichment of senescent Vδ2pos T cells in CLM patients is not only induced by patients’ aging but also by the toxicity of CHT that further accelerates the accumulation of CD57pos TEMRA cells highly dysfunctional in their anti-tumor activities. These results are important to both predict the clinical outcome of CLM and to optimize those protocols of cell cancer immunotherapy employing unconventional Vδ2pos T cells.

Diagnosis and treatment progress of Hodgkin lymphoma

Hodgkin lymphoma (HL) is a kind of malignant tumors originating from lymphoid hemopoietic tissues and often involves lymphatic system. HL is a kind of highly curable lymphomas, and the assessment of prognostic factors is important for the diagnosis and treatment of this disease. In recent years, the international research focuses on the reasonable and individualized comprehensive treatment mode of radiotherapy and chemotherapy, the exploration of new drugs and new chemotherapy protocols, in order to further improve the survival rate of patients. Staging criteria from several research organizations have played the guiding role in the therapeutic strategy of risk adjustment. Some researches have proposed low toxic and effective combined chemotherapy regimens, radiotherapy and new targeted drugs guided by positron-emission tomography. Combined with the National Comprehensive Cancer Network (NCCN) in 2017 guidelines, this paper reviews the progresses of clinicopathological manifestations, differential diagnosis and treatment regimens of HL. Key words: Lymphoma, non-Hodgkin; Neoplasm staging; Targeted therapy; Combined chemotherapy; Prognosis

Abstract P1-15-10: A prospective multicenter real-world study on neoadjuvant treatment and clinical outcome in TNBC patients

Abstract Introduction Controversy exists with regards to the optimal regimen for neoadjuvant chemotherapy (NAC) of TNBC. Platinum-based regimens seem to be more active in TNBC improving pCR rates significantly. But adding platinum to an anthracycline/taxane chemotherapy regime comes at the expense of greater toxicity. Its impact on survival and long-term-outcomes remains undetermined. Practical guidelines vary across leading international professional societies. In this real-world multicenter study neoadjuvant regimens, pCR rates and survival were evaluated. Material and methods This study was conducted from 2012-2017 in six certified breast cancer centers in the region of Hanover, Germany, including rural and urban populations by using a personal questionnaire and data from the medical records. All patients with primary TNBC (ER&amp;lt;1%, PR&amp;lt;1%, Her2/neu 0, 1+ or 2+ FISH/CISH negative) and no evidence of distant disease were eligible. Results 143/217 patients (66%) received NAC and 74/217patients (34%) adjuvant chemotherapy. 63/143 (44%) patients achieved pCR. 23/63 (35%) received platinum-based NAC and 40/63 (65%) received chemotherapy without platinum. In 80 patients pCR was not achieved. 12/80 patients received platinum and 68/80 non platinum-based NAC. pCR was significantly higher among patients with platinum-based chemotherapy (chi-square, p &amp;lt; 0.003). 20/23 patients who achieved pCR received NAC containing anthracycline/taxane/carboplatin, 3/23 patients received a taxane/carboplatin-based regime. Treatment discontinuation was seen in 12/35 (34%) patients receiving platinum-based NAC vs 15/108 (14%) in non-platinum-based NAC. Mean follow up was 17 months (1-70months). A significant difference in OS (p=0.007) and DFS (p=0.001) was seen for patients with a pCR. Conclusion Our trial confirms that platinum based NAC achieves significantly higher rates of pCR in patients with TNBC. pCR was associated with significantly longer DFS and OS. The CALBG protocol (CALBG 40603) was the preferred choice of treatment regimen followed by the GeparSixto protocol. In our study the pCR rate was comparable to that of both trials in which pCR rates of 60% (CALBG 40603) and 53% (GeparSixto) were achieved. However, in our trial 34% of the patients discontinued treatment due to toxicity. Therefore these protocols should be used in carefully selected patients. In a real world setting less toxic chemotherapy regimens achieved a pCR rate of 37%. In terms of toxicity and adherence to chemotherapy, these regimens are reasonable alternative options. In daily care close monitoring of treatment response is essential during NAC. In patients who have a rapid clinical response to platinum-free NAC the benefit of adding platinum is questionable. In contrast, the addition of platinum seems to be appropriate in those patients who show only limited response under NAC. Citation Format: Kuehnle E, Kaur P, Siggelkow W, Luebbe K, Schrader I, Uleer C, Noeding S, Noeding K-H, Noesselt T, Arfsten M, Busch C, Krentel N, Hillemanns P, Dörk T, Park-Simon T-W. A prospective multicenter real-world study on neoadjuvant treatment and clinical outcome in TNBC patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-10.

Gemcitabine-oxaliplatin first-line chemotherapy in locally advanced and metastatic gallbladder cancer - results from a tertiary centre in North India

Introduction: In view of encouraging results of ABC-02 trial in advanced biliary tract cancer, we aimed to evaluate efficacy of gemcitabine-oxaliplatin chemotherapy in our patients with locally advanced/ metastatic gallbladder cancer (GBC). Methods: Retrospective analysis of prospectively maintained database of patients with locally advanced and metastatic GBC(July 2015- December 2017) was performed. Inclusion criteria - histologically proven locally advanced GBC(≥T3 or N2 disease) or metastatic GBC, no prior chemotherapy, ECOG status≤2, normal hematologic, renal and hepatic functions. Chemotherapy regimen included injection Gemcitabine 1250mg/m2 infusion on days 1 and 8 and oxaliplatin 100mg/m2 on day 1 every 3 weeks. Primary endpoints were overall survival(OS), progression-free survival(PFS) and R0 resection rate in those given preoperative chemotherapy. Secondary endpoints were response rate and toxicity of chemotherapy regimen. Results: Total of 52 patients received chemotherapy(mean age: 52 years, 73% females) of which preoperative chemotherapy was given in 38.5 %(n=20) and palliative chemotherapy in 61.5%(n=32). Median OS was 8.3 months and median PFS was 4.7 months. Complete response was seen in 1.9%, partial response in 11.5%, stable disease in 21.2% and progression in 65.4%.In locally advanced group, 30%(n= 6/20) underwent R0 resection. R0 resection was possible in 85.7% (6/7) patients who showed response to chemotherapy. Patients who underwent surgery had significantly better OS(p< 0.01) and PFS(p=0.01). Conclusion: Combination chemotherapy with gemcitabine-oxaliplatin showed good response rate in a select subgroup of patients. Curative surgery was feasible in majority of those who had good response. Patients who underwent curative resection had significant improvement in survival.

Is There A Role of Ovarian Ablation Using Radiotherapy in the Era of Precision Medicine?

Management of Carcinoma breast has evolved over decades from Radical mastectomy to present day breast conservation surgeries and reconstructive surgeries, from 2D radiation therapy technique to present day IMRT/IGRT and Brachytherapy techniques, from toxic chemotherapy regimen to addition of taxanes and targeted therapy. Carcinoma breast is extensively studied to better the treatment options available and also to address the increasing incidence in young women. Ovarian Suppression did not take prime role in the management of cancer breast since it was mainly seen in perimenopausal who mostly attain amenorrhea after adjuvant chemotherapy and in postmenopausal women. Over the decades the incidence of carcinoma breast in young, premenopausal women has been on the rise owing to lifestyle changes, early detection by awareness programmes. Considering the changing population, the concept of ovarian suppression needs to be revisited and explored.

Toxicity of chemotherapy regimens in advanced and metastatic pancreatic cancer therapy: A network meta-analysis.

This network meta-analysis is adopted in order to compare the toxicity of different chemotherapy regimens in the treatment of advanced/metastatic pancreatic cancer (PC). Randomized controlled trials (RCTs) about different chemotherapy regimens for advanced/metastatic PC were included in this network meta-analysis using Cochrane Library and PubMed electronic databases. The network meta-analysis was performed to combine direct and indirect evidence in order to calculate the odd ratios (OR) and draw a surface under the cumulative ranking (SUCRA) curve. A total of 19 RCTs were enrolled in this network meta-analysis including 12 chemotherapy regimens (Gemcitabine, Gemcitabine + S-1 [tegafur], Gemcitabine + nab-paclitaxel, Gemcitabine + Capecitabine, Gemcitabine + Cisplatin, FOLFIRINOX [oxaliplatin + irinotecan + fluorouracil + leucovorin], Gemcitabine + oxaliplatin, Gemcitabine + irinotecan, Gemcitabine + Exatecan, Gemcitabine + pemetrexed, Gemcitabine + 5-FU, S-1). The incidence of anemia of Gemcitabine + Capecitabine regimen was higher compared with Gemcitabine regimen, Gemcitabine + pemetrexed regimen exhibited the highest incidence rates of anemia and neutropenia; while Gemcitabine + S-1, Gemcitabine + Cisplatin and FOLFIRINOX regimens exhibited the highest incidence rates of neutropenia. However, S-1 regimen exhibited lower incidence rates of leukopenia and thrombocytopenia. Moreover, the incidence rates of nausea/vomiting and rash of Gemcitabine + S-1 regimen were higher compared with Gemcitabine regimen, while Gemcitabine + Cisplatin regimen had the highest incidence rate of nausea/vomiting. This study demonstrated that the hematologic toxicity of S-1 regimen was the lowest, while Gemcitabine regimen exhibited the lowest incidence rate of non-hematologic toxicity, providing guidance for the treatment of advanced/metastatic PC.

Topical issues of chemoradiotherapy for oropharyngeal squamous cell carcinoma: the efficiency and toxicity of chemotherapy regimens with the goal of radiomodification

Topical issues of chemoradiotherapy for oropharyngeal squamous cell carcinoma: the efficiency and toxicity of chemotherapy regimens with the goal of radiomodification

Hematologic Cancer Pain

Hematologic cancers represent about 10% of new cancer diagnoses annually in the United States and account for a comparable number of US cancer deaths each year. These patients experience an array of acute and chronic pain syndromes that appreciably impair their quality of life. The pathogenesis, management, and complications of multiple myeloma, lymphoma, and leukemia are reviewed to provide a better understanding of the underlying pain processes. Skeletal-related events due to bony involvement, including pain, pathologic fractures, hypercalcemia, and spinal cord compression, along with renal insufficiency, represent a significant portion of complications faced by multiple myeloma patients. Opioids continue to be the foundation of cancer analgesia in accordance with the World Health Organization three-step analgesic ladder. Many of the long-term complications in lymphoma patients are due to treatment with toxic chemotherapy regimens along with radiation. Many of the complications seen in leukemia are nonspecific and common to cancer and its treatment in general. Bone pain is common for a number of reasons in leukemia, typically manifesting as a throbbing deep and dull ache. An array of pain syndromes develop from diagnosis through cancer survival that command a multifaceted management approach. This review contains 7 tables, 3 figures and 40 references.

The significance of multi-line chemotherapy for advanced gastric cancer: A retrospective analysis.

Palliative chemotherapy is known to benefit patients with advanced gastric cancer by palliating symptoms and improving survival. The aim of the present study was to evaluate the efficacy and toxicity of chemotherapy regimens that are commonly used in patients with advanced or recurrent gastric cancer. Patients with advanced or recurrent gastric cancer who were treated by at least two chemotherapy regimens between May 2006 and July 2014 at Zhejiang Cancer Hospital (Hangzhou, China) were retrospectively investigated. Survival was evaluated using the Kaplan-Meier method. A total of 248 patients were reviewed, and 158 were evaluated in the final analysis, with a median age of 57 years and a Karnofsky performance status score of ≥80. The median progression-free survival (PFS) time was 168 days for first-line chemotherapy, 96 days for second-line chemotherapy, and the median overall survival (OS) time was 356 days. Further analysis revealed that patients with the disease controlled [complete response (CR) + partial response (PR) + stable disease (SD)], no matter whether they received first-or second-line chemotherapy, may have had an improved OS compared with patients with disease progression (PD). Patients who were treated with >2 lines of chemotherapy had an improved OS compared those who ceased treatment following failure of the second-line chemotherapy. The cycle number of chemotherapy that patients received was associated with OS. The site of the primary and metastatic tumors was also associated with OS. Other factors, including gender, age, histological type, whether a radical operation was received, and chemotherapy regimens, had no evident association with survival. The toxicities were generally tolerated. Taken together, the results from the present study have demonstrated that an increased cycle number of effective chemotherapy may prolong the survival of patients with advanced gastric cancer. Differences among the chemotherapy regimens had no clear correlation with survival.

Trends in Hospital Cost, Length of Stay, Mortality, and Complication Rates in Patients with Acute Myeloid Leukemia in Teaching Versus Non-Teaching Hospitals: Data from the Nationwide Inpatient Sample from 1999-2013

Background: Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults and represents a heterogeneous group of clonal hematopoietic stem cell disorders with varying prognosis based on cytogenetic and host factors. Success in treatment of AML is thought to have only improved modestly in recent decades. We aimed to evaluate trends in hospital cost, length of stay, in-hospital mortality, and complication rates in adult patients admitted with active AML. We also sought to elucidate differences in these outcomes in teaching versus non-teaching institutions.Methods: Using ICD-9 codes for acute myeloid and acute monocytic leukemias, all adult admissions with a primary diagnosis of active AML between 1999-2013 were identified from the Nationwide Inpatient Sample (NIS). Admission information including length of stay (LOS), total charges, and mortality were extracted. Total cost was adjusted for inflation using data from the U.S. Bureau of Labor Statistics. ICD-9 codes were selected to reflect the most common etiologies of in-hospital complications such as clostridium difficile infection (CDI), bacteremia, sepsis, pneumonia, venous thromboembolism (VTE), neutropenic fever, candidiasis, urinary tract infection (UTI), and acute respiratory failure. Rates of these complications were determined over the 15-year interval and compared in subsets of teaching and non-teaching hospitals. Rates of bone marrow transplant were also queried.Results: We identified 51,684 admissions (weighted N = 247,747) with a primary diagnosis of AML from 1999-2013. Most of the admissions were at teaching hospitals (N = 32,982; weighted N = 158,952). Overall in-hospital mortality was determined to be 19.54%. LOS (days) was found to be longer in teaching (21.04 ±0.10) than in non-teaching (12.25 ±0.11) hospitals (p = .0001). Total charges were also greater in teaching ($157,709 ±1,089) versus non-teaching ($79,167 ±965) hospitals (p = .0001). Of note, after correcting for age, multivariate analysis yielded higher mortality in teaching than in non-teaching hospitals (OR = 1.11, CI: 1.04-1.19). Rates of CDI, bacteremia, neutropenic fever, sepsis, acute respiratory failure, and VTE were higher in teaching hospitals (p < .0001). On the other hand, rates of UTI were lower in teaching (7.31%) than in non-teaching (8.31%) hospitals (p=.0026). Rates of pneumonia and candidiasis did not have a statistically significant difference when comparing the two settings. Bone marrow transplant was more frequently performed at teaching (1.36%) than in non-teaching hospitals (0.56%) (p=.0001). Over the 15-year interval, in-hospital mortality has declined by greater than one third for all AML admissions (p <. 0001). Rates of nearly all of the complications, excluding candidiasis, but including CDI, neutropenic fever, bacteremia, UTI, pneumonia, VTE, and acute respiratory failure have increased during this interval, however. Total charges increased during this time period from $66,678 (±1,567) in 1999 to $197,439 (±4,532) in 2013 (p = .0001), which was greater than the expected inflationary increase to $93,235 over the same time period.Conclusions: Most admissions for AML occurred at teaching institutions. This may be due to increased resource requirements to care for this patient population. In-hospital mortality appears to have improved markedly from 1999-2013 for all admissions for AML, which may be a testament to well-established chemotherapy guidelines, use of less toxic chemotherapy regimens in the elderly, and standardized preventative practices such as the use of high-efficiency particulate air filtration and prophylactic antibiotics. On the other hand, rates of nearly all measured complications have increased during this interval. Given the opposite trend in mortality, we believe this may be in part due to improved surveillance and reporting. Rates of mortality as well several complication rates appear to be higher in teaching than in non-teaching institutions, which may be due to increased medical complexity and more aggressive therapy offered at teaching institutions. Further research is required to determine what additional factors and practice differences are contributing to these discrepancies. Total charges were higher at teaching institutions, which may be due to increased LOS, complication rates, medical complexity and resource consumption. DisclosuresNo relevant conflicts of interest to declare.

Risk adapted single-agent dactinomycin or carboplatin for second-line treatment of methotrexate resistant low-risk gestational trophoblastic neoplasia

ObjectiveTo evaluate the outcome of patients treated with second-line chemotherapy for methotrexate-resistant low-risk GTN at the Sheffield Centre, UK between 2001 and 2015, including the novel use of single-agent carboplatin as a strategy to reduce exposure to combination chemotherapy. Methods392 low-risk GTN patients were treated with first-line methotrexate. The selection of chemotherapy regimen following methotrexate-resistance depended on the volume of residual disease as indicated by the serum hCG value at the time, with patients switching to either single-agent dactinomycin at an hCG level<150IU/L from 2001–2010 and <300IU/L since 2010, or to combination treatment with etoposide/dactinomycin (EA) above these thresholds. In order to reduce exposure to more toxic combination chemotherapy regimens, our treatment policy was revised in 2011, with the recommendation of single-agent carboplatin as an alternative to EA at hCG levels >300IU/L. Results136 (35%) of 392 received second-line chemotherapy following methotrexate-resistance. 59 patients received single-agent dactinomycin with 53 (90%) patients achieving complete hCG response, 3 patients requiring combination chemotherapy or surgery, and 3 patients subsequently spontaneously resolving. 56 patients received EA chemotherapy with hCG complete response in 50 (89%) patients, and the remaining 6 patients were cured with further multi-agent chemotherapy or surgery. With carboplatin, 17/21 (81%) achieved an overall complete hCG response rate, with 4 patients requiring third-line EA. Carboplatin was well tolerated with no significant alopecia; myelosuppression was the most significant toxicity. Overall survival for all patients was 100%. ConclusionThese data show the continued excellent outcomes for methotrexate-resistant low-risk patients treated with single-agent dactinomycin or EA. Our experience with carboplatin is promising and provides an alternative regimen for methotrexate-resistant low-risk disease that avoids alopecia and in-patient treatment.

T-cell lymphomas, a challenging disease: types, treatments, and future

T-cell lymphomas are rare and aggressive malignancies associated with poor outcome, often because of the development of resistance in the lymphoma against chemotherapy as well as intolerance in patients to the established and toxic chemotherapy regimens. In this review article, we discuss the epidemiology, pathophysiology, current standard of care, and future treatments of common types of T-cell lymphomas, including adult T-cell leukemia/lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma, aggressive NK/T-cell lymphoma, and cutaneous T-cell lymphoma.

Abstract A16: The tyrosine phosphatase PRL3 as a novel drug target in T-cell acute lymphoblastic leukemia.

Abstract The aggressive and unpredictable behavior of T-cell acute lymphoblastic leukemia (T-ALL) presents a major clinical challenge in both the pediatric and adult setting. The challenges associated with T-ALL are two-fold: 1) the recently improved cure rate for primary T-ALL is largely attributed to highly toxic chemotherapy regimens that have both short- and long-term adverse effects in patients, and 2) chemotherapy is often ineffective against relapsed T-ALL, which has a dismal 5-year survival rate of &amp;lt;30% in children and &amp;lt;10% in adults. The development of new and better chemotherapies requires a detailed understanding of the genes and pathways that drive T-ALL malignancy. We have completed an unbiased cell transplantation screen using a zebrafish model of T-ALL and in excess of 6,000 adult recipient animals to identify molecular targets that promote T-ALL progression and relapse. Single leukemic cells were grown in syngeneic recipient fish and animals were assessed for differences in growth, leukemia propagating cell frequency, and therapy resistance. Serial transplantation experiments then followed evolution within 48 single-cell clones, identifying 6 clones that evolved increased LPC frequency and/or elevated growth potential. Comparative genomic hybridization arrays were used to identify recurrent amplifications associated with clonal evolution, and identified Protein Tyrosine Phosphatase 4A3 (PRL3) as being genomically amplified in 30% of clones with elevated LPC frequency and growth. Real-time quantitative PCR showed that 90% of clones with high LPC frequency and growth expressed high levels of PRL-3, suggesting additional genetic pathways likely activate PRL3. PRL-3 was also genomically amplified in a subset of human T-ALL and highly expressed in 58% of primary T-ALL patient samples, suggesting that this phosphatase is an important and previously undefined driver of human T-ALL. PRL3 has not been previously associated with leukemia progression or survival, although it is expressed in Multiple Myeloma and Acute Myelogenous Leukemia. PRL3 knock-down in human T-ALL significantly reduced the viability of cell lines in vitro and in xenograft models (p&amp;lt;0.0001). Additionally, the specific PRL3 inhibitor 1-(2-bromobenzyloxy)-4-bromo-2-benzylidene rhodanine strongly induced apoptosis of PRL3-expressing T-ALL cells in a dose-dependent manner. PRL3 inhibition also killed T-ALL cell lines that were resistant to dexamethasone, the standard chemotherapy for T-ALL, suggesting that therapies that inactivate PRL3 will be useful for the treatment of refractory and relapse disease. We have also identified several FDA-approved, general phosphatase inhibitors that have potent anti-PRL3 activity and are capable of killing T-ALL cells in vitro. Current work is focused on moving these inhibitors into pre-clinical testing using patient-derived xenografts. Phospho-profiling approaches are also being used to identify the substrates of PRL3 tyrosine phosphatase activity that are critical to T-ALL survival and may represent new, tractable drug targets for the treatment of T-ALL and other types of leukemias. Citation Format: Jessica Blackburn, Aleksey Molodtsov, Riadh Lobbardi, Finola Moore, David Langenau. The tyrosine phosphatase PRL3 as a novel drug target in T-cell acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A16.