Aggressive Combination Chemotherapy Research Articles

Pramlintide: A Novel Therapeutic Approach for Osteosarcoma through Metabolic Reprogramming.

Simple SummaryOutcomes for patients with osteosarcoma have remained stagnant for more than 3 decades. Novel therapeutic agents are desperately needed. Osteosarcoma cells often express abnormal form of the p53, p63, and p73 genes, which promote glucose uptake, cell glycolysis, and rapid proliferation. Pramlintide, an FDA-approved drug for type 2 diabetes, interfered with tumor glycolysis leading to decreased cell growth and increased cell death. When we injected Pramlintide into osteosarcoma tumor nodules of the mice, the tumors were significantly smaller after 21 days while the control tumors continued to grow. Tumor hypoxia was also decreased. This is the first report showing the potential efficacy of Pramlintide against osteosarcoma, indicating that Pramlintide may be a novel therapeutic approach for patients with relapsed osteosarcoma.Despite aggressive combination chemotherapy and surgery, outcomes for patients with osteosarcoma have remained stagnant for more than 25 years, and numerous clinical trials have identified no new therapies. p53 deletion or mutation is found in more than 80% of osteosarcoma tumors. In p53-deficient cancers with structurally altered p63 and p73, interfering with tumor cell metabolism using Pramlintide (an FDA-approved drug for type 2 diabetes) results in tumor regression. Pramlintide response is mediated through upregulation of islet amyloid polypeptide (IAPP). Here, we showed that osteosarcoma cells have altered p63, p73, and p53, and decreased IAPP expression but have the two main IAPP receptors, CalcR and RAMP3, which inhibit glycolysis and induce apoptosis. We showed that in osteosarcoma cells with high- or mid-range glycolytic activity, Pramlintide decreased cell glycolysis, resulting in decreased proliferation and increased apoptosis in vitro. In contrast, Pramlintide had no effect in osteosarcoma cells with low glycolytic activity. Using a subcutaneous osteosarcoma mouse model, we showed that intratumoral injection of Pramlintide-induced tumor regression. Tumor sections showed increased apoptosis and a decrease in Ki-67 and HIF-1α. These data suggest that in osteosarcoma cells with altered p53, p63, and p73 and a high glycolytic function, Pramlintide therapy can modulate metabolic programming and inhibit tumor growth.

Predicting the Risks of Aggressive-Intent Chemotherapy Toxicity in Older Patients With Lymphoma: A Prospective Observational Pilot Study

IntroductionLymphoma is a disease of older patients and while treatment is subtype specific, curative or aggressive intent combination chemotherapy is often recommended. However, there has been limited evidence on which to base treatment decisions for older adults. Our objectives were to assess the utility of risk stratification measures and serial functional tests in predicting chemotherapy toxicity and as well the feasibility of conducting these in older adults undergoing chemotherapy for lymphoproliferative disorders. Materials and MethodsThis prospective cohort study recruited lymphoma patients 70 years or older planned for systemic chemotherapy. The Cancer and Aging Research Group (CARG) risk stratification tool and Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) were calculated at baseline. The Clinical Frailty Scale (CFS), Charlson Comorbidity Index score, grip strength and gait speed test, and toxicity events, were assessed at baseline and serially throughout treatment. Sarcopenia was calculated on CT scans at baseline, midway through treatment, and 1-month after completion of therapy. The primary endpoint was to assess the feasibility of applying these measures in busy ambulatory clinics. These measures were also correlated with clinical outcomes including ≥grade 3 adverse events (AEs), hospitalizations and emergency department visits, dose changes or delays, and overall survival. ResultsIn total, 30 patients were enrolled (mean age 78.1 ± 6.4 years), of whom 20 were treated with curative intent. A total of 16 patients (53%) experienced grade ≥3 AEs, 9 (56%) of which led to a chemotherapy delay. On univariable analyses, CFS score, a high CARG score, medium to high CRASH score, and the gait speed were associated with grade ≥3 AEs, while only CFS remained significant on multivariable analysis. On univariable analysis, patients with a medium to high risk CRASH score were more likely than low risk patients to have an unplanned emergency department visit or hospitalization. ConclusionsThe CFS seems to predict toxicity in this cohort study, with gait speed, CARG and CRASH scores being potentially additional predictive methods of evaluation.

Immunotherapy of Neuroblastoma: Facts and Hopes.

While the adoption of multimodal therapy including surgery, radiation, and aggressive combination chemotherapy has improved outcomes for many children with high-risk neuroblastoma, we appear to have reached a plateau in what can be achieved with cytotoxic therapies alone. Most children with cancer, including high-risk neuroblastoma, do not benefit from treatment with immune checkpoint inhibitors (ICI) that have revolutionized the treatment of many highly immunogenic adult solid tumors. This likely reflects the low tumor mutation burden as well as the downregulated MHC-I that characterizes most high-risk neuroblastomas. For these reasons, neuroblastoma represents an immunotherapeutic challenge that may be a model for the creation of effective immunotherapy for other "cold" tumors in children and adults that do not respond to ICI. The identification of strong expression of the disialoganglioside GD2 on the surface of nearly all neuroblastoma cells provided a target for immune recognition by anti-GD2 mAbs that recruit Fc receptor-expressing innate immune cells that mediate cytotoxicity or phagocytosis. Adoption of anti-GD2 antibodies into both upfront and relapse treatment protocols has dramatically increased survival rates and altered the landscape for children with high-risk neuroblastoma. This review describes how these approaches have been expanded to additional combinations and forms of immunotherapy that have already demonstrated clear clinical benefit. We also describe the efforts to identify additional immune targets for neuroblastoma. Finally, we summarize newer approaches being pursued that may well help both innate and adaptive immune cells, endogenous or genetically engineered, to more effectively destroy neuroblastoma cells, to better induce complete remission and prevent recurrence.

ERCC overexpression associated with a poor response of cT4b colorectal cancer with FOLFOX-based neoadjuvant concurrent chemoradiation.

Colorectal cancer (CRC) of the clinical tumor stage T4b (cT4b) refers to advanced tumors with direct invasion of adjacent structures and the tumors are considered unresectable. Despite advancements in aggressive surgery and combination chemotherapy, the prognosis of cT4b CRC remains poor. Optimizing the therapeutic sequence administered to patients with cT4b CRC to improve clinical outcomes is crucial. In the present study, patients with unresectable cT4b and nodal stage N1-2 CRC were investigated at a single institution. A total of 20 consecutive patients were treated with pre-operative concurrent chemoradiation by using 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) since February 2015 and were regularly followed up until March 2020. Due to their poor response to concurrent chemoradiation (CCRT) with FOLFOX, the chemotherapy regimen was changed to irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as the second-line neoadjuvant treatment. Genetic alterations, such as microsatellite instability (MSI), were documented, and the expression levels of excision repair cross-complementing group 1 (ERCC1) and ERCC2 were examined. Of the 20 patients, the tumors of 14 patients (70%) became resectable after FOLFIRI administration. The median duration between the last date of radiotherapy and surgery was 32.7 weeks (range, 10.1–59.3 weeks). Of note, 4 of the 14 patients with resectable tumors (28.6%) achieved a pathologic complete response. The median overall survival and progression-free survival were 27.5 months (range, 12–39 months) and 27.5 months (range, 8–39 months), respectively. The cancerous specimens of all of the patients (100%) exhibited ERCC2 overexpression and 18 specimens (90%) had ERCC1 overexpression. Only one tumor (5%) exhibited high MSI. The present study indicated that ERCC overexpression associated with the poor response of FOLFOX-based CCRT and FOLFIRI after FOLFOX-based CCRT failure may have a potential role in conversion to resectable tumors by neoadjuvant treatment in cT4b CRC. However, a further prospective study with more patients is required to improve the precision of the conclusions.

Long-Term Survival and Cure in Distant Metastatic Breast Cancer

Background: Previous data showed that distant metastatic breast cancer (MBC) might be curable in up to 3% of the cases in selected patients, mostly young, with good performance status and with low-volume metastatic disease, mainly by an aggressive multidisciplinary approach including aggressive combination chemotherapy regimens. These long-lasting responses question the belief that MBC is wholly incurable. This study evaluates the rate of long-term survivors and potentially cured patients in an unselected cohort of MBC patients. Methods: We analyzed the data from 342 patients in whom distant MBC was diagnosed from 1990 to 2011. For this study, we defined a metastatic disease survival (MDS) of 9 years as inclusion criterion for long-term survivorship. Results: Eighteen patients (5.3%) were long-term survivors (MDS: 126 months; range, 108–300 months). The rate of long-term survivors was equally distributed over time (1990–1999: 4.3% vs. 2000–2011: 5.9%, p = 0.63). Compared to patients who had a lower MDS, long-term survivors had significantly more often primary MBC (p = 0.005) and hormone receptor-positive carcinomas (p = 0.015). Age at MBC diagnosis, presence of visceral metastases, and limited number of metastatic sites at the time of MBC diagnosis appeared to have no significant impact on long-term survival. Long-term survival was not associated with the use of chemotherapy (50.0% vs. 65.7% in the control group, p = 0.21). Eight patients (2.3%) developed a complete remission and presented with no evidence of disease at the time of last follow-up (MDS: 234.5 months). Conclusion: Since long-term survivors in MBC comprise a relatively heterogeneous group, the factors that lead to the quite rare and felicitous case of long-term survival or even cure can hardly be evaluated systematically. Some patients may be considered cured of their disease. This fraction may be small, but the chance of survival, and even of cure, truly exists. Perhaps we must accept that the factors contributing to long-term survival remain an enigma. It appears, however, that aggressive chemotherapy is not the only key factor to long-term remission.

Abstract 2594: A multigene recurrence signature identifies highly proliferative tumors that escape immune surveillance in early stage lung and pancreas adenocarcinoma

Abstract Background: Accurately predicting recurrence in early stage cancer patients may be used to avoid unnecessary therapies with significant side effects or deliver early interventions that can improve outcomes. Both early stage lung (LAc) and pancreatic adenocarcinoma (PDAc) are high-recurrence cancers for which biomarkers that can quantify this risk could benefit patients. In stage I LAc only a small percentage of stage IB patients receive chemotherapy, while more patients may derive additional benefit if identified. In PDAc, patients with the most aggressive stage I-II disease could derive benefit from early aggressive combination chemotherapy if identified. Methods: Training and test sets (n=10) were selected by random sampling RNA-seq expression data into groups of 65% and 35% respectively. Cox proportional hazards and Kaplan-Meier analysis were used to predict RFS and OS. Maximally selected rank statistics were used to designate low and high-risk signature groups. Subgroup analysis was performed using multivariate Cox methods. Pathway analysis was performed with Webgestalt. RNA-seq expression data for LAc and PDAc was obtained from the cancer genome atlas and gene microarray data from NCBI GEO. All statistical analyses and plots were generated in R v3.2. Results/Discussion: An unbiased analysis of RNA-seq data identified a 19-gene consensus signature (19-GCS) that is upregulated in tumors and able to predict LAc stage I RFS. Multivariate analysis demonstrated its independence as a prognostic factor and efficiency in independent validation sets. Pathway analysis identified proliferation and immune surveillance as altered pathways in 19-GCS high-risk (sHR) compared to low-risk (sLR) tumors. In confirmation of this finding Cyclin D was downregulated while Cyclin E/A/B were upregulated in sHR tumors. Moreover, the 19-GCS was correlated with proliferation markers Ki-67 and PCNA and showed universal correlation with G2/M phase-specific genes. The expression of MHC Class I and II subunit markers were lost in sHR tumors as were specific MHC-related genes. Moreover, the expression of tumor-infiltrating immune cell-specific markers were largely lost in sHR tumors. The 19-GCS was better able to predict RFS and OS in PDAc than in LAc, and consistent with PDAc's severity, more patients were identified as high-risk. Gene expression analysis identified the same molecular characteristics in sHR PDAc as in sHR LAc. Analysis of clinical outcomes for both LAc and PDAc demonstrated that sHR predicted progressive disease in response to both primary and followup therapy. Overall, the 19-GCS identifies highly proliferative early stage lung and pancreatic tumors with impaired MHC mechanisms that shield them from immune-mediated destruction. This deadly combination leads to recurrence and poor clinical outcomes that might be avoided if identified early. Citation Format: Nathaniel Weygant, Jiannan Yao, Dongfeng Qu, Parthasarathy Chandrakesan, Guangyu An, Courtney W. Houchen. A multigene recurrence signature identifies highly proliferative tumors that escape immune surveillance in early stage lung and pancreas adenocarcinoma [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 2594.

Germ Cell Tumor Ovary: an Institutional Experience of Treatment and Survival Outcomes.

Malignant germ cell tumors (GCT) of the ovary account for 2-3% of all ovarian neoplasms and occur mostly in the second and third decade of life. Over the past three decades, survival rates for germ cell tumors have dramatically improved, coincident with more aggressive surgical staging and combination chemotherapy. Although there are several studies describing ovarian GCT and fertility-preserving surgery in the western population, there is very little Indian data. We present our experience of germ cell tumor ovary in the Department of Surgical Oncology, King George's Medical University over the last 5years with special emphasis on treatment outcome and role of fertility preservation surgery. A retrospective review of medical records of patients with ovarian germ cell tumors, treated at our center from January 2012 to December 2016, was performed. Epidemiological and clinical profile of patients was reviewed. Clinical stage of presentation, neoadjuvant treatment, surgical treatment, and adjuvant treatment data were analyzed, and treatment outcome data was recorded. Patient follow-up was done to ascertain disease-free interval, treatment outcome, ability to conceive following fertility-preserving surgery, and quality of life. A total of 39 patients with ovarian germ cell tumor were treated during this period. Their median age at diagnosis was 22years (range 11-65years) and most common mode of presentation was abdominal lump without ascites. Around 36.8% (n= 14) patients had conservative surgery with preservation of opposite ovary and uterus. Most patients (71.1% n= 27) received neoadjuvant chemotherapy due to advanced disease in form of ascites or large mass, and five of these patients were amenable to fertility-preserving surgery after chemotherapy. Nine out of the fourteen patients have had return of menstrual function after a mean period of 3.5 + 0.5months. One patient who underwent fertility-preserving surgery has delivered healthy children after treatment. Stage distribution for stage I to IV was as follows: 15.4% (n= 6), 35.9% (n= 14), 46.2% (n= 18), and 2.6% (n= 1), respectively. Dysgerminoma was the commonest histology (37.1% n= 13) followed by teratoma (22.9% n= 8). 17.1% (n= 6) patients had recurrence, with a median time to recurrence 16months (range 5.5 to 37months) and they were treated with second-line chemotherapy. Germ cell tumor of the ovary is an eminently treatable disease and selected patients can be managed with fertility-preserving surgery. BEP is the most effective chemotherapy regimen. Disease-free survival rates in these patients are quite high and recurrences can be managed with second-line chemotherapy.

The quality of life and the occurrence of dysphagia in patients with head and neck cancer following combined oncological treatment

Introduction. The localisation of head and neck carcinomas influences the functions of speech, breathing, and swallowing, which, in turn, directly affect the patient’s quality of life. The poor prognosis associated with tumours of this type indicates that aggressive combined therapy protocols, including surgery, chemotherapy, and radiotherapy, should be implemented. Such treatments commonly cause acute toxicity and short- and long-term swallowing complications. Therefore, even though they can contribute significantly to survivorship, these treatments reduce the quality of life. The aim of this study was to analyse the influence of applied combined oncological treatments on the occurrence of dysphagia in patients with head and neck cancer and on their quality of life. Methods. A group of 135 patients with head and neck carcinomas treated with combined protocol (surgery, chemotherapy, and radiotherapy) in the Lukaszczyk Oncological Centre in Bydgoszcz between 2010 and 2014 was analysed. The quality of life and subjective evaluation of the swallowing function was assessed using the MDADI ( M.D. Anderson Dysphagia Inventory ). Results. A statistically significantly worse subjective evaluation of the quality of life was observed in the patients with dysphagia, who had undergone surgery with radiotherapy, compared to those who had not had surgery (p = 0.03). A statistically significantly worse subjective quality of life evaluation was found in patients who had the most locally advanced tumours (T4) (p = 0.04) as well as the highest stages of the disease (S3 and S4) (p = 0.04). A statistically significantly worse subjective quality of life with dysphagia was also seen in patients who had chemoradiotherapy in comparison to those who had radiotherapy alone (p = 0.01). A statistically significantly worse subjective quality of life with dysphagia was observed in the patients whose tumours were localised in the oral part of the pharynx and larynx compared to those patients with other tumour localisations (p = 0.02). A statistically significantly worse subjective quality of life with dysphagia was identified in the patients who had a higher dose of radiation (exceeding 45 Gy) in the upper oesophageal sphincter compared to those patients who had a lower dose (below 45 Gy) in the UES (p = 0.01). Conclusions. In patients with dysphagia, surgical treatment negatively impacts their subjective quality of life. Moreover, the pattern of radiation therapy affects the quality of life in patients with dysphagia. A radiation therapy plan that spares the upper oesophageal sphincter by using a dose of less than 45 Gy may prevent dysphagia. Dysphagia is also associated with tumour localization, tumour stage, and local advancement of the disease.

CD30 Is a Potential Therapeutic Target in Patients with HTLV-1 Associated Adult T-Cell Leukemia/Lymphoma Presenting Outside of Japan.

AbstractAbstract 2706 Objective:Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell malignancy associated with human T-cell lymphotropic virus -1 (HTLV-1) infection. Four clinical subtypes are recognized including acute/lymphomatous (aggressive) or chronic/smouldering (indolent). For the aggressive subtypes the median overall survival is 6 months despite aggressive combination chemotherapy. Novel therapeutic targets against CD25, CD52, and NF μB have shown preliminary activity in ATLL. Recently, the chemokine receptor 4 (CCR4) antibody (KW-0761) was approved in Japan based on a phase II overall response rate of 50% and median overall survival of 13.7 months in 28 patients with relapsed/refractory ATLL. CD30 (Ki-1) is a marker of immune activation expressed on lymphocytes, and is an emerging target in lymphoma. The novel antibody-drug conjugate brentuximab vedotin targets CD30 and has shown efficacy in Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL). While CD30 positive ATLL is infrequent in Japanese ATLL patients, ranging from 12.1% to 19.4%, the prevalence of CD30 positive ATLL outside of Japan has not been extensively studied. Patients and Methods:To investigate the prevalence of CD30 expression and its importance in ATLL outside of Japan we conducted a retrospective review of all patients who underwent treatment or consultation for ATLL at our institution between 1998 and 2012. Individual chart review was performed to report the clinical presentation, pathological features, and outcomes. Pathology review of CD30 expression status was conducted if specimens were available. The CD30 (Ber-H2) antibody from Ventana was used on automated platforms per manufacturer’s instructions. Specimens were determined to be positive if the CD30 expression was >20% by an expert hematopathologist (AC). Results:We identified 50 patients with ATLL. Patient characteristics were: median age 54 (range 30–82); male:female 19:31; Caribbean-39, American-6, Western African-2, Peruvian-2, and Greek-1. Subtype of disease at diagnosis was: Acute/Lymphomatous—41 and Chronic/Smouldering—9. Thirty-six of 50 (72%) patients’ samples had been tested at least once for CD30. Eighteen patients (50%) were reported positive. Of all cases reviewed (N=50), eight had pathology available for confirmatory review. Of those, five patients remained positive, 1 patient was reclassified as positive after initially being reported as negative, and two remained negative. The median overall survival of all patients was 13 months. In the subset who had CD30 status assessed the median overall survival for CD30 negative and positive ATLL was 18 and 45 months respectively (p=0.116). Conclusions:CD30 expression on normal lymphocytes is rare. Our retrospective data suggests that ATLL patients presenting outside of Japan may demonstrate CD30 positivity at a higher prevalence compared to Japanese reports. In pre-clinical studies of CD30 positive ATLL, SGN-35 has been shown in vitro and in vivo to demonstrate similar cytotoxicity compared to ALCL (Maeda et al. Cancer Sci 2010). Novel strategies are clearly needed to improve the outcome of ATLL despite recent advances. Therefore, CD30 testing may be considered in ATLL as a novel target for future research strategies. [Display omitted] Disclosures:Matasar:GSK: Research Funding; Genentech: Consultancy. Straus:Seattle Genetics: Consultancy. Zelenetz:GSK: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Gilead: Consultancy; Sanofi Aventis: Consultancy; Cephalon: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Amgen: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding.

Need for Patient Reported Outcomes (PRO) in Adult Acute Lymphoblastic Leukemia (ALL)

AbstractAbstract 4704 Background:Acute lymphoblastic leukemia (ALL) accounts for about 20% of adult leukemias and occurs with increasing frequency in adults after 50 years of age. Symptoms include bone and joint pain, increased bruising and bleeding, weakness or tiredness, fever, loss of appetite and weight loss, paleness, pain or feeling of fullness below the ribs, pinpoint red spots on the skin (petechiae), lymphadenopathy, and night sweats. For adult ALL, appropriate induction therapy can result in complete remission in 60–80% of patients, with between 35–40% of adult patients expected to survive 2 years. Aggressive induction combination chemotherapy requires effective supportive care to manage infection, bleeding, and other concomitant issues. These treatment-related symptoms, combined with the disease symptoms argue for measurement tools that provide a clear understanding of the impact on the patients’ health-related quality of life (HRQOL), record changes over time, and can demonstrate clinical benefit in trials. The objective of the study was to describe and assess the PRO instruments that can be used in adult ALL setting, summarize PRO’s in clinical trials, and evaluate the labeling potential when using these measures for patient self-report in adult ALL, particularly as it relates to selecting and implementing PROs and interpreting data. Methods:An in depth literature review was conducted. Elsevier and Medline databases were consulted using Embase platform. Studies were included if they were: published from 01/01–12/11, in English, and included terms related to leukemia disease and PROs. A thorough review of abstracts was performed using selection criteria including those where PRO instruments were used and/or psychometric validation was performed. References for selected articles were used to identify other relevant sources. Clinical trials.gov was also used to search for adult ALL trials from 2001–2011. Results:Very few studies were found specific to HRQOL and adult ALL, although the broader search for HRQOL in leukemia found 15 PRO instruments: 4 leukemia-specific, 5 on treatment-related impact, and 6 on general cancer HRQOL. (Table 1a). 1245 studies in clinicaltrials.gov were found using the search term adult acute lymphocytic leukemia. This was reduced to 11 studies when QOL was requested as an endpoint and age was restricted to 21 and above. Of those, there was 1 observational study and 10 intervention studies. HRQOL instruments were not identified in 8 of the studies. The QLQ-C30, EQ-5D, HADS, and NCCN distress thermometer were used in 1 phase 2 and 2 phase 3 studies (Table 1b). No specific labeling claims were found in labels made to date for adult ALL related compounds to FDA or EMA.Table 1aSummary of PRO instruments used in leukemiaPRO instruments# Items/QuestionsValidation (Yes/No)Leukemia specificMedical Research Council QLQ-Leu32NFACT-Leu44YLIP (Life Ingredient Profile)51YEORTC QLQ CLL 1616OngoingTreatment relatedQLQ Leu BMT32NFACT-BMT50YDBMT (Demands of BMT Recovery Inventory)59NFACT-BRM40YHADS14YCancer specificEORTC QLQ C3030YFACT-G27YFLIC22YCARES (CARES –SF)139 (59)YNCCN distress thermometerSingle item scaleYTable 1b:Summary of PRO instruments used in ongoing adult ALL clinical trialsPRO InstrumentsComparatorPopulation/PhaseHADS, NCCN distress thermometerKetamine HCl/PlaceboAdult ALL in remission, recurrent adult ALL with neuropathic pain/P3EORTC QLQ C30, EQ-5Dinotuzumab ozogamicin/FLAG (fludarabine, cytarabine, and G-CSF) or HIDAC (high dose cytarabine) or cytarabine and mitoxantroneRelapsed or Refractory CD22-Positive ALL/P3EORTC QLQ C30lenalidomide + dexamethasoneRefractory B-cell lineage ALL or Relapse after 2 lines of treatment/P2 Conclusions:Several instruments contain only general cancer related symptoms, but omit most ALL specific symptoms. While there are some leukemia specific measures, most ongoing adult ALL trials are using only cancer specific instruments. The lack of leukemia-specific measures in adults with ALL, argues for the need to understand the patient's burden of disease and impact of ALL treatment. A detailed evaluation of existing instruments and instrument development/modification is needed with a goal of influencing patient-centered outcomes and product differentiation. Disclosures:Mehta:Sanofi: Employment. Joulain:Sanofi: Employment, Equity Ownership. Hageman:Sanofi: contract employment Other. Trask:Sanofi: Employment.

Usefulness of Flow Cytometric Immunophenotyping for Bone Marrow Staging in Patients With Mantle Cell Lymphoma After Therapy

We evaluated the role of flow cytometric immunophenotyping (FCI) in the assessment of bone marrow (BM) specimens in 104 patients with mantle cell lymphoma (MCL) following treatment with aggressive combination chemotherapy. Of the patients, 77 had no morphologic or FCI evidence of MCL, 13 had morphologic and FCI evidence of MCL, and 14 patients were morphologically negative but FCI showed CD5+ clonal B-cells (M-/FCI+). Retrospective cyclin D1 immunostaining was positive in 3 of 12 M-/FCI+ cases. Clinical staging and follow-up showed that 4 of 12 patients had concurrent extramedullary involvement by MCL, 5 patients subsequently became M+ for MCL in BM (within 2-24 months), and 3 patients had no recurrent MCL on follow-up. We conclude that FCI is more sensitive than morphologic examination of BM at the time of restaging in patients with MCL and that positivity by only FCI in BM often correlates with concurrent disease or subsequent relapse.

Nonmetastatic Ewing’s Sarcoma of the Lumbar Spine in an Adult Patient

Although the spine is frequently involved in metastatic Ewing's sarcoma, primary involvement of the spine, beside sacrum, is much less frequent, especially in adult patients. Because of the low incidence of these tumors, there are currently no clinical guidelines outlining their management and a multitude of therapeutic strategies have been employed with varying success. The definitive management of Ewing's sarcoma of the spine, as in other locations, could include the combination of three main modalities: aggressive surgery, radiotherapy, and combined chemotherapy. Whenever possible, en bloc spondylectomy or extralesional resection is preferable, providing a better oncological result with a longer survival and a better preservation of the spine biomechanics. This is the lesson we learned about the case, we present here, of nonmetastatic lumbar localization by Ewing's sarcoma in as adult patient.

Uveitis: When a Vitrectomy Is More Than Just a Treatment

PURPOSE: Nasal T/NK lineage lymphoma, previously known as lethal midline granuloma, is common among Oriental, Native-American, and Hispanic patients and is invariably associated with Epstein-Barr virus. Nasal localization, local necrosis, angioinvasion, and aggressive behavior are hallmarks of the disease. Ophthalmologic symptoms and signs may precede lymphoma diagnosis or complicate its disease course. We aim to define the incidence and disease pattern of ophthalmic involvement.DESIGN: Retrospective single-institution consecutive interventional case series.METHODS: Records of all lymphoma patients from 1996 to 2000 were retrieved from a computer database, and the primary sites and lineage were reviewed. Nasal T/NK lymphoma was defined by a combination of morphology, positive CD3ε and CD56 expression, in situ hybridization staining for Epstein-Barr virus expressed RNA (EBER), and negative staining for B cell markers (CD20 and CD79a).RESULTS: Thirty-five consecutive patients with T/NK lymphoma were identified. Primary nasal or nasopharyngeal disease was found in 24 patients. Six (25%) of the 24 patients suffered from vision-threatening complications of two distinct categories, namely uveitis/vitritis and orbital infiltration. The former preceded the diagnosis of lymphoma in two patients and also led to novel ocular complications like rhegmatogenous retinal detachment and macular hole that were successfully managed by ocular surgery. In four patients, orbital extension of lymphomatous disease accompanied biopsy-proven in-field disease relapse. Generally, the prognosis is grave, but remission can still be achieved with aggressive combined chemotherapy and radiotherapy.CONCLUSION: Both oncologists and ophthalmologists should be aware of ocular complications when dealing with known or suspected cases of T/NK lymphoma at diagnosis and relapse. Regular ophthalmic assessment of these patients is warranted.

Rituximab Added to Aggressive Chemotherapy Improves the Outcome of Patients with Follicular Lymphoma, Grade 3 and Results In Survival Comparable to Diffuse Large B-Cell Lymphoma.

AbstractAbstract 2810The survival of patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma is improved when rituximab is combined with chemotherapy. However, little is known about the outcome of patients with follicular lymphoma, grade 3 (FL-3), since these patients are generally excluded from DLBCL trials and often from trials evaluating treatment of follicular lymphoma. We therefore performed a retrospective study to evaluate the results of rituximab-based therapy for FL-3. An analysis of the Nebraska Lymphoma Study Group database allowed us to identify patients with FL-3 who were treated with aggressive combination chemotherapy regimens with and without the addition of rituximab. The progression-free survival (PFS) and overall survival of these patients were compared to patients with DLBCL who were treated with similar aggressive chemotherapy regimens combined with rituximab. Patients who were not treated with anthracycline-containing or mitoxantrone-containing regimens were excluded from analyses. We identified 60 FL-3 patients who were treated with aggressive chemotherapy regimens, combined with rituximab, between Feb. 1999 and Jan. 2009. The median age was 56 years (range 37–87 years). There were 27 males and 33 females. The performance status was 0–1 in 80%, the LDH was elevated in 15%, 68% had stage III-IV disease, and 13% had at least 2 sites of extranodal disease. Fifteen patients (25%) had bulky disease (≥5 cm) at diagnosis. The results of treatment for these patients were compared to 144 FL-3 patients treated with aggressive chemotherapy regimens without rituximab between June 1983 and Jan. 1999, and to 341 patients with DLBCL who were treated with aggressive chemotherapy regimens combined with rituximab between Sept. 1996 and Jan. 2009. The treatment outcomes for these three groups of patients are displayed in the table.5-yr Estimate (95% CI)8-yr Estimate (95% CI)Log-Rank p-valueProgression-Free Survival0.04FL-3 with rituximab65% (50–77)45% (23–65)FL-3 without rituximab42% (34–50)33% (26–41)DLBCL with rituximab53% (47–58)47% (40–54)Overall Survival0.06FL-3 with rituximab85% (72–92)71% (54–82)FL-3 without rituximab68% (59–74)54% (46–62)DLBCL with rituximab64% (58–69)56% (48–63)A multivariate analysis (accounting for older patients, and more patients with elevated LDH, extranodal disease, and bulky disease in the DLBCL group) revealed that patients with FL-3 who were not treated with rituximab had a significantly higher risk of disease progression or death (RR 1.75; p=0.02). There were no significant differences in PFS when comparing patients with FL-3 and those with DLBCL who were treated with aggressive chemotherapy regimens and rituximab. Follicular lymphoma, grade 3 patients treated without rituximab had inferior overall survival, when compared to patients treated with rituximab (RR 1.58), although this difference was not significant (p=0.16). The multivariate analysis also revealed no significant differences in survival when patients with FL-3 who received rituximab were compared to similarly treated patients with DLBCL (p=0.50). In conclusion, this analysis demonstrates that the outcome of treatment for patients with FL-3 who are treated with aggressive chemotherapy regimens is improved when rituximab is added to therapy. In the “rituximab era” the outcome of patients with FL-3 is comparable to DLBCL. Disclosures:Vose:Millennium Pharmaceuticals, Inc.: Research Funding.

Optimal treatment for recurrent/metastatic head and neck cancer

While a large proportion of patients presenting with stage I and II squamous cell carcinoma of the head and neck (SCCHN) will remain disease free after single modality treatment, the majority of patients presenting in a more advanced disease stage and very often treated with a form of combined modality treatment, will eventually relapse, either locoregionally only, at distant sites only or both. A few patients with a locoregional recurrence can be salvaged by surgery or reirradiation. However, most patients with recurrent or metastatic (R/M) disease only qualify for palliative treatment. Treatment options in these patients include supportive care only, or in addition single agent chemotherapy, combination chemotherapy or targeted therapies either alone or in combination with cytotoxic agents. Prognostic factors analysis in such patients treated with (platinum-based) chemotherapy has identified five adverse prognostic factors, which seems worthwhile to take into consideration when performing trials; one pathologic feature (tumor cell differentiation) and four clinical baseline characteristics (ECOG performance status, weight loss, location of the primary tumor and prior radiotherapy). Moreover, it has been shown that response to systemic therapy has a major impact on survival. None of the trials performed in the past, even those with a reasonable sample size, have shown that aggressive platinum-based combination chemotherapy leads to survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil. After decades without real progress, a recent European randomized trial showed that adding cetuximab, the first clinically available EGFR-directed monoclonal antibody, to a standard chemotherapy regimen (platinum/5-fluorouracil) leads to an important survival benefit and this, with support of an additional smaller study in the US, has changed practice.

Hodgkin's disease in the bone marrow

Tumor involvement of the bone marrow in patients with Hodgkin's disease may be suspected in the presence of other manifestations of advanced disease such as fever, lymphopenia, hypoalbuminemia, mixed cellular histologic type, or Stage III or IV disease by other clinical parameters. It occurs more frequently in the older age groups. When anemia, leucopenia, and/or thrombocytopenia are present and are unrelated to recent bone marrow suppressant chemotherapy, marrow involvement is likely to be present. Bone marrow examination, done by multiple trephine biopsies, provides an adequate sampling of tissue and results in a high incidence of detection of involvement by Hodgkin's disease. This manifestation of Hodgkin's disease is associated with a relatively short survival. Aggressive combination chemotherapy is necessary to produce a significant remission.

Malignant mixed müllerian tumor with malignant neuroectodermal components (teratoid carcinosarcoma) of the ovary: Report of a case with clinicopathologic findings

Malignant mixed müllerian tumor (MMMT) or carcinosarcoma of the female genital tract is a rare neoplasm. Malignant ovarian tumor composed of müllerian epithelial tumor and malignant germ cell tumor is also rare, with most cases composed of endometrioid adenocarcinoma and yolk sac tumor. Ovarian MMMT with malignant neuroectodermal components resembling immature teratoma is extremely rare. We report a case of teratoid carcinosarcoma of the ovary occurring in a 40-year-old female. The resected tumor measuring over 20 cm in diameter consisted of cystic and solid components and was very fragile. Microscopic examination showed a heterogenous mixed tumor composed of malignant epithelial, malignant mesodermal and malignant neuroectodermal components. The cells of ganglioneuroblastoma-like area were positive for neural markers (Synaptophysin, S-100 protein, neuron-specific enolase). There was no tumor immunoreactivity to alpha-fetoprotein, carcinoembryonic antigen, human chorionic gonadotropin, and inhibin. In spite of aggressive combination chemotherapy and three times of laparotomy, the patient died of disease 3 years 10 months after the initial treatment. This quite rare ovarian tumor closely resembled nasopharyngeal tumors described as 'teratoid carcinosarcoma' is biologically aggressive. We report the fourth case of ovarian teratoid carcinosarcoma. Further cases need to be accumulated to make diagnosis and to determine a successful treatment modality.

A phase II trial of promace-cytabom in previously untreated non-hodgkin's lymphoma of intermediate- or high-grade histology

Between November 1985 and June 1989 the aggressive combination chemotherapy programme ProMACE-CytaBOM was used at a community-based hospital as primary treatment for non-Hodgkin's lymphoma (NHL) of intermediate or high-grade histology in Ann-Arbor stages IB-IV. The 53 patients entering the study represented 90 per cent of all consecutive eligible patients with NHL diagnosed during the time period considered. Their median age was 54 years and median observation time was 36 months. Of 50 patients evaluable for response, 35 (70 per cent) achieved complete remission (CR), seven (14 per cent) partial remission, and five (10 per cent) were refractory. Treatment was given on an outpatient basis. Actually delivered drug doses ranged from 88 per cent to 97 per cent of the theoretical doses. Life-threatening toxicity was experienced by four patients. Treatment was stopped in three cases (6 per cent) because of toxicity and there was one treatment-related death. Actuarial 2-year disease-free survival of patients in CR was 73 per cent. Overall actuarial 3-year survival and disease-free survival were 67 per cent and 51 per cent respectively. High LDH level was a significant adverse prognostic factor both for achievement of CR (P less than 0.005) and for survival (P less than 0.0002). Age was of no prognostic importance. We conclude that ProMACE-CytaBOM is an effective, easy to administer and well-tolerated regimen for patients with aggressive NHL.

Presentation of Primary Hepatic Lymphoma (PHL) as Episodic Jaundice

Case Presentation: A 27 yr-old male with 1-year history of episodic jaundice presented with 10-kilograms weight loss and jaundice over one month. His past medical history was relevant for an episode of alcoholic hepatitis when his symptoms of jaundice initially started. On presentation, he had generalized icterus and a large firm, mildly tender nodular liver. Blood tests showed mild coagulopathy along with moderately elevated hepatic enzymes. CT of the abdomen showed a 10 cm liver mass along with 2 smaller lesions in the left hepatic lobe. There was significant intrahepatic biliary ductal dilatation along with compression and thrombosis of portal vein. The excisional biopsy led to the diagnosis of diffuse B cell lymphoma based on immunoperoxidase staining. PET scan showed enhancing mass in the medial and lateral segments of left lobe of the liver. There was an increased activation in the area of retroperitoneal lymph nodes and the vertebral bodies T12 and L1 likely representing local metastases without any evidence of distant metastases or another primary. In view of the age and functional status, it was decided to give him curative doses of chemotherapy. After one cycle of chemotherapy his weight and functional status improved. Discussion: PHL is reported to occur with increased frequency in patients with chronic hepatitis C infection. Imaging studies reveal solitary, or less often, multiple masses in the liver. The predominant histology is B-cell lymphoma, most commonly diffuse large cell type. Most patients are treated with chemotherapy, with some physicians employing a multimodality approach incorporating surgery and radiotherapy with chemotherapy. The prognosis is variable, with good response to early aggressive combination chemotherapy regimens. The overall survival after surgical management can reach up to 10 yrs. PHL is a rare entity. It represents 0.4% of extranodal Non Hodgkin's lymphoma (NHL) and 0.016% of all NHL. The liver is involved in 15–27% in NHL. Hence it is important to rule out the involvement of other organ sites or disseminated disease to liver before considering the possibility of PHL. As with the majority of PHL, the lymphoma in the above case originated from B lymphocyte lineage. Also, the role of episode of alcoholic hepatitis in initiation of primary hepatic lymphoma is uncertain and it needs to be investigated.

Adenocarcinoma of the uterine cervix with choriocarcinomatous metastasis

Background. Nongestational choriocarcinoma, in very rare instances, has been described as a component of other malignancies with a tendency for a very poor prognosis. Case. A 55 year old woman was diagnosed with adenocarcinoma of the cervix, and incompletely treated with only external beam radiation. Adjuvant radical hysterectomy demonstrated no residual tumor, but the patient developed a tumor metastasis mimicking a pulmonary artery thrombus which by histology and immunohistochemistry was pure choriocarcinoma. While chemotherapy was successful in achieving a complete remission, the patient succumbed to complications of her pulmonary metastasis. Conclusion. Choriocarcinomatous dedifferentiation of cervical adenocarcinoma is extremely rare, with only one other case reported in the literature. While the prognosis for patients with such a tumor is generally poor, aggressive combination chemotherapy may be of benefit in some.