Long-term Complete Remission Research Articles

Extranodal NK/T-cell lymphoma: a review of literature and case report

Extranodal NK/T-cell lymphoma – a rare lymphoproliferative disease characterized predominantly by extranodal localization, aggressive course and low efficiency of conventional chemotherapy. Clinical presentation is diverse and depends on tumor lesion localization. In this article, a literature review and case report of patient with generalized extranodal NK/T-cell lymphoma with bone marrow involvement, unusual intracranial tumor localization, tumor leukemization and central nervous system-leukemia were presented. Adequate treatment strategy made it possible to achieve long-term complete remission in a patient with poor prognosis.

Efficacy of Focal Adhesion Kinase Inhibition in Combination with Dasatinib in BCR-ABL1 Acute Lymphoblastic Leukemia

Introduction: BCR-ABL1+ B-progenitor acute lymphoblastic leukemia (Ph+ B-ALL) is a highly aggressive disease that is often refractory to currently available therapies. Our previous genomic profiling studies have identified loss-of-function or dominant negative mutations in IKZF1, encoding the lymphoid transcription factor Ikaros, in over 80% of Ph+ ALL. In addition, deletion of CDKN2A, which encodes the INK4A and ARF tumor suppressors, is observed in approximately half of all cases (Mullighan et al., 2008). Alterations of IKZF1 are associated with poor outcome despite the use of tyrosine kinase inhibitors (TKIs). Ikzf1 alterations, including Ikaros isoform 6 (IK6), result in the acquisition of stem cell-like features, enhanced self-renewal, expression of adhesion molecules, and transcriptional upregulation of focal adhesion kinase (FAK), resulting in increased adhesion in vitro and in vivo, and decreased sensitivity to TKIs (Churchman, Cancer Cell, in press). VS-4718 is a potent, selective, and orally bioavailable FAK inhibitor currently under evaluation in a phase 1 clinical trial in subjects with various solid tumors, however in vivo efficacy in hematological malignancies had not been evaluated. Targeting FAK with VS-4718 is an attractive approach to abrogate the adhesive phenotype of IKZF1-altered leukemic cells potentially enhancing the effects of dasatinib in the treatment of high-risk BCR-ABL1 B-ALL.Methods: We examined the efficacy and mechanisms of FAK inhibition using VS-4718 as a single agent and in combination with dasatinib in vitro and in vivo in a range of xenograft and genetically engineered mouse models of BCR-ABL1 ALL. Each model had concomitant deletion of Arf which is observed in approximately 50% of human cases.Results: A pre-clinical in vivo trial of dasatinib and VS-4718 combination therapy in a murine C57Bl/6 Arf-/- BCR-ABL1 pre-B cell model resulted in a marked increase in survival in both IK6-expressing and non-IK6 cohorts of mice, and one complete long-term remission in the IK6-expressing group. Further, we showed increased efficacy of VS-4718 and dasatinib, compared to either agent alone, against two highly aggressive human Ph+ IK6-expressing B-ALL xenografts in vivo, with decreased infiltration of leukemic cells in bone marrow and spleens demonstrating a synergistic effect of the VS-4718/dasatinib combination. In vitro cell viability was reduced with induction of apoptosis at increasing concentrations of VS-4718 as a single agent, and further potentiated the effects of dasatinib in cytotoxicity assays using human xenografted and murine leukemic cells.VS-4718 profoundly diminished the ability of BCR-ABL1-expressing cells to form cell-matrix adhesions in vitro, as evident by the reduced adherence to fibronectin monolayers and bone marrow stromal cells. VS-4718 almost completely abolished the colony-forming potential of BCR-ABL1-expressing murine pre-B cells with and without Ikzf1 alterations at drug concentrations that do not affect cell viability suggestive of a reduction in self-renewal.Calvarial imaging of mice transplanted with Ikzf1-altered BCR-ABL1 leukemic cells and treated with VS-4718 alone in vivo revealed a discernible reduction in adhesion in the intact bone marrow niche of Prrx1-Cre; LSL-tdTomato recipient mice. VS-4718 treated leukemic cells localized to Prrx1-expressing perivascular endothelial cells and exhibited round morphology in contrast to the typical spindle-like appearance of Ikzf1-altered pre-B cells adhering to the bone marrow stroma, suggesting that VS-4718 treatment abolished the aberrant leukemic cell-stromal adhesion induced by Ikaros alterations in vivo.Conclusions: Direct inhibition of FAK with VS-4718 attenuates the adhesive, stem-like properties of IKZF1-altered BCR-ABL1 leukemic cells that contribute to the poor prognosis of patients treated with currently available therapies. Targeted FAK inhibition is thus a promising avenue for improving the response of BCR-ABL1 ALL to dasatinib, particularly in refractory cases harboring IKZF1 alterations. These data support the clinical development of VS-4718 in combination with dasatinib in Ph+ B-ALL. DisclosuresShapiro:Verastem: Employment, Equity Ownership. Pachter:Verastem: Employment, Equity Ownership. Weaver:Verastem: Employment, Equity Ownership. Mullighan:Amgen: Honoraria, Speakers Bureau; Cancer Science Institute: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Research Funding; Incyte: Consultancy, Honoraria. Off Label Use: The FAK inhibitor VS-4718 for the treatment of BCR-ABL1 acute lymphoblastic leukemia in preclinical models.

Long-Term Survivors after Stem Cell Transplantation in Multiple Myeloma: Bone Marrow Minimal Residual Disease, PET/CT and Immunological Status

Abstract Introduction: Multiple myeloma (MM) is considered an incurable disease. Best results are obtained with autologous stem cell transplantation (ASCT). The achievement of complete remission (CR) is the crucial step for a prolonged survival. Unfortunately, even with the use of new regimens, the vast majority of patients will ultimately relapse. In fact, with conventional chemotherapy, ASCT or allogeneic stem-cell transplantation (alloSCT), only 1‰, 10% and 15%, respectively are alive and in continued CR beyond 10 years in the best circumstances. The aim of the present research was to evaluate the proportion of patients in long-term CR after stem-cell transplantation, describing the different aspects related to minimal residual disease (MRD) and immunological correlative studies. Methods: We analyzed the medical records of 160 patients who underwent single melphalan-based ASCT from March 31th 1994 to December 31th 2010, allowing at least 5 years of follow up from diagnosis (median follow-up of 8 years), as well as 58 patients who had received an alloSCT over a 28-year period. Bone marrow (BM) samples from the alive CR patients beyond 5 years were analyzed to assess MRD using multiparameter flow cytometry (MFC) with Euroflow 8-color consensus panel. Serum free-light chains (FLC) and immunoglobulin heavy/light chains (HLC) (The Binding Site) were assayed by immunonephelometry. A whole-body PET/CT (Siemens) was also performed to evaluate extramedullary and bone disease. Furthermore, a detailed panel of surface cell markers by MFC was also developed to evaluate B, T and NK cell compartments, among other immune cell subpopulations in BM and/or peripheral blood. Results: Twenty patients (20/160; 12.5%) were alive and in continuous CR after ASCT beyond 5 years; nine (5.7%) remained in CR for more than 10 years. In the alloSCT group, 6 out 58 patients (10.3%) were in CR beyond 5 years (3 of them for more than 10 years). Remarkably, two patients were in CR after 20 and 28 years after ASCT and alloSCT, respectively. Fourteen long survivors after ASCT (70%) had received maintenance therapy. These regimens were mainly interferon (8 patients), followed by thalidomide (3) or thalidomide plus bortezomib (3). None patient showed increased uptake of FDG by PET/CT suspicious of MM activity, neither in bone lesions nor previous plasmacytomas. However, in the vast majority of patients (16/22; 72.7%) there were stable lytic lesions, usually with sclerotic borders. Unspecific findings, particularly lymph nodes with unspecific FDG uptake, were described in 28.6%. Fourteen out of 20 patients after ASCT (70%) and 2 after alloSCT (33.3%) showed oligoclonal bands (OB) in serum and/or urine, differents from the original monoclonal paraprotein by immunofixation. Among the 22 evaluated patients, all but 2 were negative by MFC for MRD in BM. These two patients were in stable CR, with evidence of OB in serum, considering the clone found unrelated to the original one. The aberrant plasma cell population (CD38+/++, CD56+, CD27-, CD19-, CD45-, CD81-, CD117+) was found to a frequency of 0.09% and 0.004% BM cells. Other 4 patients showed a population of plasma cells with some aberrant markers expression; two of them also showed OB. All patients showed normal serum FLC ratio except one patient after alloSCT. Levels of IgG and IgA HLC were also normal, except in one patient each. Six patients had higher IgM HLC ratio than normal, all of them showing OB. We also investigated whether T cell clonal expansion could be also involved. Indeed, patients with OB showed a higher diversity of TCR Vb over-represented, preferentially 13.1 and 17, suggesting a potential oligoclonal expansion of the T cell response. Characterization of TCR repertoire of the long survivors also indicated a higher involvement of the CD8+ compared to CD4+ T cells. In BM, the expression of the co-inhibitory receptor PD-1 on CD8+ T cells was elevated in active MM compared to MGUS and long survivors suggesting that exhausted PD1+CD8+ T cells increase in active MM and recover to normal levels in long survivors. Conclusions: There are a small proportion of long-term survivors after SCT in MM. MRD studies are negatives, but some false positives could be observed by MFC when OB are present. PET invariably showed metabolic CR with stable bone lesions. Our results support that oligoclonal humoral and cellular responses may play an important role in the disease control over the years. Disclosures No relevant conflicts of interest to declare.

An Unordinary Recurrence of Urothelial Bladder Carcinoma in the Colon Presenting as Hematochezia

The conventional route of recurrence and metastasis in primary urothelial cell carcinoma of the bladder is through lymphatics and hematogenous system with regional lymph nodes, lungs, liver, brain and bone being the most commonly involved sites. Invasive urothelial cancers could also spread locoregionally to surrounding organs including female genital tract, prostate and gastrointestinal tract especially colo-rectum. However, recurrence of this cancer inside the colon in the absence of locoregional invasion, and after achieving complete long-term remission is extremely unusual. A review of the literature revealed a single case reported by Yang et al. of an urothelial cancer recurrence in the colon with mixed urothelial/colonic malignant pathology [1]. Herein we report the second case, to our knowledge, of an urothelial cell bladder carcinoma that recurred inside the colon in the form of a mass causing hematochezia, which on pathology and immunohistostaining proved to be primarily of urothelial rather than colonic origin. 67 year old male heavy smoker with stage III (T3a, N0, M0) transitional cell carcinoma of the bladder had undergone radical cystectomy, neo-bladder reconstruction and adjuvant chemotherapy following initial diagnosis. He poved repetitively to have no evidence of disease until he presented 4 years later with intermittent hematochezia and anemia. Colonoscopy revealed a fungating, ulcerated mass in the sigmoid colon suggestive of a primary colon cancer (fig 1). Pathology disclosed high grade/poorly differentiated carcinoma invading the colonic mucosa that surprisingly favored an urothelial origin. Upon further immunostaining, final diagnosis of a metastatic high-grade urothelial carcinoma was confirmed by positive cytokeratin (CK) 7 stain (specific for urothelial cells) and negative villin and CDX2 stains that are both specific for gastrointestinal differentiation (fig 2). CT scan of abdomen and pelvis, and PET scan did not reveal any other sites of cancer recurrence. Patient received a tailored chemotherapy and responded appropriately.Figure 1Figure 2This case illustrates a rare kind of recurrence of urothelial cancer in the form of a colonic mass resembling primary colon cancer. This unordinary way of recurrence could pose a clinico-pathological diagnostic challenge in distinguishing this disease treated basically with chemotherapy, from a primary colon cancer managed primarily by surgical resection. Immunohistochemical stains are essential for an accurate diagnosis. Heightened awareness is of utmost importance in such patients with history of urothelial cancer in order to appropriately tailor further treatment strategies that differ between primary and secondary colonic tumors.

Sa1481 Outcomes of Endoscopic Therapy for Barrett'S High Grade Dysplasia and Early Esophageal Cancer in a Community Hospital Setting

Sa1481 Outcomes of Endoscopic Therapy for Barrett’S High Grade Dysplasia and Early Esophageal Cancer in a Community Hospital Setting Riad H. Al Natour*, Andrew Catanzaro, Eugene Zolotarevsky, Anthony T. Debenedet, Naresh T. Gunaratnam Internal Medicine, St. Joseph Mercy Hospital, Ann Arbor, MI; Huron Gastroenterology Associates, Ypsilanti, MI Background: Barrett’s high grade dysplasia (BEHGD) and early (T1a) esophageal adenocarcinoma (eEAC) can be successfully treated endoscopically by radiofrequency ablation (RFA) and mucosal resection (EMR). These treatment modalities have been proven successful in high-volume academic medical centers. Effectiveness of endoscopic therapy for BEHGD and eEAC in a community hospital setting is unknown. Methods: All consecutive patients (pts) with BEHGD and eEAC treated endoscopically at our institution between August 2007 and August 2014 were prospectively enrolled in a database. All pts had biopsy proven BEHGD or eEAC confirmed by two expert GI pathologists. All pts were treated by EMR and/or RFA every 2-3 months until complete eradication of dysplasia (ED) and intestinal metaplasia (CEIM). Once therapeutic end-point was reached, pts were enrolled in surveillance program with serial endoscopies per protocol. Results: A total of 194 pts underwent endoscopic therapy for dysplastic BE. Sixty-four (33%) pts had advanced dysplasia (BEHGD 34 and eEAC 30) with median length Barrett’s of 4 cm (Interquartile range (IQR), 2-7 cm). Forty-eight pts had EMR. Median treatment interval was 9 months (IQR, 4-24 months). Median follow up was 3 years (IQR, 1.4-4.4 years). Fifty-nine (92%) pts maintained long-term remission of dysplasia and 52 (81%) pts intestinal metaplasia. One pt failed to regress BEHGD six months into therapy. Dysplasia was downstaged in 4 (6%) pts. Relapse after CEIM occurred in 9 (14%) pts with NDBE (6), BELGD (1), BEHGD (1) and eECA (1). After retreatment, CEIM was again achieved in 5 pts, and ED in 3 pts. Pts with long segment BEO6 cm were more likely to relapse (OR 4.2; pZ0.03). There were no procedure-related esophageal perforation, severe hemorrhage, or complications requiring hospitalization. Twelve pts (10 having prior EMR) developed a symptomatic stricture, which responded to dilatation. There was no procedure or disease-related mortality. Conclusions: Endoscopic management of BEHGD and eEAC can be provided effectively in a community hospital setting. Complete eradication and long-term remission of dysplasia and intestinal metaplasia can be achieved in majority of pts without major morbidity or mortality.

Targeted salvage lymphadenectomy in patients treated with radical prostatectomy with biochemical recurrence: complete biochemical response without adjuvant therapy in patients with low volume lymph node recurrence over a long-term follow-up.

BackgroundCholine positron emission tomography/computed tomography (PET/CT) represents an option in restaging of prostate cancer patients with disease relapse after local treatment. The present study assess whether salvage resection of lymph node metastases detected on choline PET/CT imaging in prostate cancer patients with biochemical recurrence after radical prostatectomy can result in a long-term complete biochemical remission, without adjuvant therapy.MethodsWe analysed 13 patients with prostate specific antigen (PSA) recurrence (PSA median 1.64 ng/ml, range 0.5-9.55) after radical prostatectomy and suspicious lymph nodes (median 1; range 1–3) detected on [11C]choline and [18F]fluoroethylcholine PET/CT scans. An open salvage lymphadenectomy of positive lymph nodes in a PET/CT scan and nearby lymph nodes was carried out. We examined PSA outcome without adjuvant therapy; defined complete biochemical remission as PSA <0.01 ng/ml. Histological and PET/CT findings were compared.ResultsTen of 11 patients with histologically confirmed lymph node metastases showed a PSA response. Three of ten patients with single lymph node metastases had a complete biochemical remission (median follow-up 72 months, range 31.0-83). In five cases with single lymph node metastasis PSA decreased <0.02 ng/ml. Histologically confirmed 13 of 16 metastasis suspicious lymph nodes. No lymph node metastases were detected in two patients. All of the additionally removed 30 lymph nodes were correctly negative.ConclusionsThis is the first confirmation of a complete biochemical remission after PET/CT guided secondary resection of a single lymph node metastasis in prostate cancer patients with biochemical recurrence after radical prostatectomy, over the long-term (>6.5 years), without adjuvant therapy. In order to improve these promising results, longer-term studies with more patients are required.

Cytotoxic T-Lymphocyte Analysis of Aggressive Types of Adult T-Cell Leukemia/Lymphoma Patients with Complete Remission after Intensive Combination Chemotherapy

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-I). Most ATLL cells are CD4 and CCR4 positive, and CD8 negative. ATLL is classified into 4 clinical subtypes: smoldering, chronic, acute, and lymphoma. Acute and lymphoma type ATLLs, which are aggressive types, have a very poor prognosis. In Japan, aggressive ATLLs are commonly treated by intensive chemotherapies, such as VCAP-AMP-VECP, modified LSG15 therapy, and biweekly CHOP therapy. Recently, an anti-CCR4 monoclonal antibody (mogamulizumab) was approved for relapse and refractory ATLL in Japan. Mogamulizumab induces a highly potent antibody dependent cellular cytotoxicity, suggesting the importance of immuno-cell therapy for treatment of ATLL. We report here the extremely interesting results of aggressive ATLL patients with long-term survival and complete remission (CR) after activation of cellular immunity against ATLL cells following intensive chemotherapies.Patients and Methods: We retrospectively evaluated 46 cases of aggressive ATLLs diagnosed at the Nagasaki Genbaku Hospital between January 2001 and August 2011. Of these, 7 patients had long-term survival greater than 3 years with CR after intensive chemotherapies. Four of these 7 patients had human leukocyte antigen (HLA)-A02:01 or HLA-A24:02, and were investigated using anti-HTLV-I specific cytotoxic T-lymphocyte (CTL) analysis. The HTLV-I provirus load in peripheral blood was also analyzed.Results: Table 1 summarizes the characteristics of 7 aggressive type ATLL patients with long-term survival. Four patients were male and 3 were female. Six patients were classified as lymphoma type and 1 as acute type ATLL. The median age was 68 (range, 60–78) years. The median survival period from the onset of the disease was 111 (range, 36–165) months. In all 7 patients, the CD4/CD8 ratio reversed during, or shortly after, chemotherapy and CD8 predominance continued for more than 1 year (range, 13–165 months, median 24 months). Three patients had herpes virus infection during chemotherapy and reversal of the CD4/CD8 ratio appeared just after herpes virus infection in 2 of these patients. These observations suggested that HTLV-I specific CTLs were induced and contributed to the treatment of ATLL in these patients. An HTLV-I specific CTL analysis currently is available in patients with HLA-A02:01 and HLA-A24:02. Three of 7 aggressive ATLL patients with long-term survival and CR had HLA-A02:01 and 1 had HLA-A24:02. Therefore, HTLV-I specific CTL analysis and HTLV-I provirus load in the peripheral blood were performed in all 4 patients. Each patient was examined twice, once in 2012 and once in 2014. HTLV-I specific CTLs were detected in all patients (Table 2 and Figure 1). Although all patients maintained CR for, HTLV-I proviruses were detected in the peripheral blood in all patients (Table 2). This phenomenon was observed both in 2012 and in 2014 (Table 2 and Figure 1).Conclusions: The findings from this study suggest that HTLV-I specific CTLs can be induced in patients with aggressive types of ATLL. In patients having long survival with CR, these CTLs can contribute to treatment and may play a roll inhibiting the relapse of ATLL. The development of efficacious methods to induce HTLV-I specific CTLs in individual ATLL patients may lead to improved outcomes for aggressive types of ATLL.Table 1Summary of aggressive type ATLL patients with long-term survival and complete remissionPatientNo.GenderAge(year)Survival fromthe onset of ATLL (months)Duration ofCD4/CD8 reversal(months)Herpes virus infection1Male69165165+2Male6814096+3Female717165-4Male6012413+5Female6111118-6Male783613-7Female655624-Table 2A Summary of HTLV-I specific CTL analysis and HTLV-I provirus load in the peripheral bloodPatient No.HLA20122014CTLHTLV-I provirusCTLHTLV-I provirus(%)(copies/1000 cells)(%)(copies/1000 cells)1A02:010.1135.40.1361.92A02:010.7824.41.5614.75A02:011.067.11.3113.37A24:022.0726.43.6427.9 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Effects of CCL3 on Osteoblast Inhibition in Myeloma-Induced Bone Disease

Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow. A common manifestation of the disease is bone destruction that caused by increased osteoclastic bone resorption and decreased bone formation. Suppression of osteoblast activity appears to persist even in patients enjoying long-term complete remission that without any detectable MM tumor cells. CCL3, also known as MIP-1α, is a pro-inflammatory and chemoline. To investigate if CCL3, a recently described osteoclast stimulatory factor,was possibly involved in the inhibition of osteoblast in MM-induced bone disease,osteoblast from BM of MM patients and healthy donors were cultured in vitro. Our results showed the proliferation and osteogenic potential of osteoblasts from MM patients were suppressed. MM-derived OBs expressed higher levels of CCR1 compared with normal controls. It’s an indication that CCL3 is able to influence OBs in MM bone disease (MBD).We cultured MM-derived OBs in osteogenic media and then stimulated them with CCL3 in the absence or presence of neutralizing antibody against CCL3. Our data suggested that CCL3 impaired matrix mineralization and suppressed osteocalcin (OCN).Gene expression analysis of osteoblastic transcription factors in CCL3-treated OBs revealed a Runx2 and Osterix downregulation. CCL3 antibody at least partially restored OBs activity with an upregulation of OCN levels and Runx2 and Osterix expression. These results showed that CCL3 may contribute to OB/OC imbalance by inhiting OBs’ dedifferentiation and function in MBD. DisclosuresNo relevant conflicts of interest to declare.

Dendrogenin_A : A Natural Liver X Receptor Modulator for the Treatment of Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is the most common type of leukemia in adults. Despite intensive research, current treatments remain unsatisfactory with only 40% of younger (<60 years) and less than 10% of older (>60 years) AML patients achieving long-term complete remission. Consequently, drugs with novel mechanism of action are urgently needed to improve the outcome of these patients. We have recently identified Dendrogenin A (DDA) as a cholesterol metabolite present in normal cells but undetectable in various cancer cell lines including AML (de Medina et al, Nat Commun, 2013). DDA, the first steroidal alkaloid identified in mammals, exhibited strong anticancer effects against different tumor models in vitro and in vivo. In this study, we investigated the antileukemic potency of DDA in AML.We demonstrated that DDA exerts potent cytotoxic effect in a large panel of AML cell lines and cytogenetically and molecularly diverse primary AML patient samples (n=50) with a median IC50 of 3.3 µM (range 1.2-10 µM). We determined that DDA triggers both apoptosis and cytotoxic autophagy on AML cells. Macroautophagy was characterized by the accumulation of autophagic vacuoles and the stimulation of autophagic flux.As opposed to conventional chemotherapies, the antileukemic effect of DDA was similarly efficient in both immature stem/progenitor CD34+CD38-CD123+ subpopulation and leukemic bulk. Interestingly, the antileukemic activity of DDA on AML patient samples was not correlated to usual prognostic factors such as adverse cytogenetic risk karyotype, clonogenic ability, white blood cells count and FLT3-ITD or NPM status.Pharmacokinetic studies revealed that both per os (PO) and intraperitoneal (IP) administration led to a good absorption with calculated bioavailability of 74% (PO) and 48% (IP), showing that these modes of administration are relevant to in vivo preclinical studies.We then examined the in vivo anti-leukemic efficacy of DDA in NOD/SCID mice injected subcutaneously with HL60 and KG1 cells. We demonstrated that daily administration of DDA (20 mg/kg IP or 40 mg/kg PO) significantly reduced KG1 and HL60 tumor growth. Immunohistochemical analysis revealed that AML xenografts from mice exposed to DDA display a 3.5 fold increase of LC3 punctated cells and a decreased P62 level highlighting that DDA induces autophagy in vivo. Furthermore, DDA significantly kills AML cells in bone marrow and brain (55±5.6% reduction of viable CD45+ cells), and strongly reduces (57±7.8%) the total cell tumor burden in bone marrow and spleen in established disease models (eg. orthotopically engraftment of HL60 cells and three primary AML patient cells via tail vein injection in NOD/SCID/IL2Rγc-deficient mice). In addition, we showed that DDA is well tolerated in mice at effective dose and spares normal hematopoietic stem/progenitor cells from healthy donor.Mechanistic studies revealed that DDA is a natural modulator of the Liver X Receptor (LXR), a nuclear receptor involved in cholesterol homeostasis, immunity and proliferation. We found that the silencing of LXRβ gene prevents the capacity of DDA to trigger both cell death and autophagy on AML cells in vitro. In addition, DDA failed to block tumor development and to trigger autophagy on LXRβ-invalidated KG1 cells xenografted on NOD/SCID mice. Moreover, DDA strongly stimulates the expression of the myeloid leukemogenesis tumor suppressors Nur77 and Nor1 through an LXRβ-dependent mechanism. Interestingly, DDA triggers the relocation of Nur77 to the mitochondria, a process associated with both apoptosis and autophagic cell death. This study provides a strong rationale to bring DDA in clinical trials for patients with AML. Disclosuresde Medina:Affichem: Employment. Bize:Affichem: Employment. Paillasse:Affichem: Employment. Noguer:Affichem: Employment. Sarry:Affichem: Equity Ownership. Silvente-Poirot:Affichem: Equity Ownership. Poirot:Affichem: Equity Ownership.

Discontinuation of infliximab therapy in patients with Crohn's disease in sustained complete remission (the STOP IT study): protocol for a double-blind, randomised, placebo-controlled, multicentre trial

IntroductionInfliximab (IFX), a monoclonal chimeric antibody against tumour necrosis factor (TNF) α, is effective for induction and maintenance of remission in moderate to severe Crohn's disease. Discontinuation of IFX maintenance...

Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity.

Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intrapleurally administered CAR T cells vastly outperformed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. After intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced antitumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4(+) T cell activation associated with a higher intratumoral CD4/CD8 cell ratios and CD28-dependent CD4(+) T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication, or persistence. The ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through "regional distribution centers." On the basis of these results, we are opening a phase 1 clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.

Therapeutic options in idiopathic burning mouth syndrome: literature review.

Introduction Burning mouth syndrome (BMS) is characterized by a burning sensation in the tongue, palate, lips, or gums of no well-defined etiology. The diagnosis and treatment for primary BMS are controversial. No specific laboratory tests or diagnostic criteria are well established, and the diagnosis is made by excluding all other possible disorders. Objective To review the literature on the main treatment options in idiopathic BMS and compare the best results of the main studies in 15 years. Data Synthesis We conducted a literature review on PubMed/MEDLINE, SciELO, and Cochrane-BIREME of work in the past 15 years, and only selected studies comparing different therapeutic options in idiopathic BMS, with preference for randomized and double-blind controlled studies. Final Comments Topical clonazepam showed good short-term results for the relief of pain, although this was not presented as a definitive cure. Similarly, α-lipoic acid showed good results, but there are few randomized controlled studies that showed the long-term results and complete remission of symptoms. On the other hand, cognitive therapy is reported as a good and lasting therapeutic option with the advantage of not having side effects, and it can be combined with pharmacologic therapy.

Cyclosporine A as a Primary Treatment for Panniculitis-like T Cell Lymphoma: A Case with a Long-Term Remission.

Subcutaneous panniculitis-like T cell lymphoma (SPTL) is a distinctive cutaneous lymphoma characterized by an infiltration of subcutaneous tissue by neoplastic T cells, similar to panniculitis. It is well-established that patients who are diagnosed with SPTL usually respond poorly to chemotherapy, showing fatal outcome. As a first line treatment for SPTL, anthracycline-based chemotherapy was most frequently used. For the treatment of SPTL, the efficacy of cyclosporine A has been recently reported in relapsed SPTL after anthracycline-based chemotherapy. However, it is still not clear whether cyclosporine A can be used as a first-line treatment against SPTL. Here, we report a case of SPTL, which achieved complete remission for nine years after first-line cyclosporine A therapy. This study suggests that cyclosporine A can induce a complete long-term remission as a first-line treatment.

Transferrin Receptor-Mediated Endocytosis: A Useful Target for Cancer Therapy

Current cancer management strategies fail to adequately treat malignancies with multivariable dose-restricting factors such as systemic toxicity and multi-drug resistance limiting therapeutic benefit, quality of life and complete long-term remission rates. The targeted delivery of a therapeutic compound aims to enhance its circulation and cellular uptake, decrease systemic toxicity and improve therapeutic benefit with disease specificity. The transferrin peptide, its receptor and their biological significance, has been widely characterised and vastly relevant when applied to targeting strategies. Utilising knowledge about the physiological function of the transferrin-transferrin receptor complex and the efficiency of its receptor-mediated endocytosis provides rationale to continue the development of transferrin-targeted anticancer modalities. Furthermore, multiple studies report an upregulation in expression of the transferrin receptor on metastatic and drug resistant tumours, highlighting its selectivity to cancer. Due to the increased expression of the transferrin receptor in brain glioma, the successful delivery of anticancer compounds to the tumour site and the ability to cross the blood brain barrier has shown to be an important discovery. Its significance in the development of cancer-specific therapies is shown to be important by direct conjugation and immunotoxin studies which use transferrin and anti-transferrin receptor antibodies as the targeting moiety. Such conjugates have demonstrated enhanced cellular uptake via transferrin-mediated mechanisms and increased selective cytotoxicity in a number of cancer cell lines and tumour xenograft animal models. In addition, incubation of chemotherapy-insensitive cancer cells with transferrin-targeted conjugates in vitro has resulted in a reversal of their drug resistance. Transferrin immunotoxins have also shown similar promise, with a diphtheria toxin mutant covalently bound to transferrin (Tf-CRM107) currently involved in human clinical trials for the treatment of glioblastoma. Despite this, the inability to translate preliminary research into a clinical setting has compelled research into novel targeting strategies including the use of nanoparticulate theory in the design of drug delivery systems. The main objective of this review is to evaluate the importance of the transferrin-transferrin receptor complex as a target for cancer therapy through extensive knowledge of both the physiological and pathological interactions between the complex and different cell types. In addition, this review serves as a summary to date of direct conjugation and immunotoxin studies, with an emphasis on transferrin as an important targeting moiety in the directed delivery of anticancer therapeutic compounds.

Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib – Analysis of prognostic factors (EORTC-STBSG collaborative study)

Long-term complete remissions remain a rare exception in patients with metastatic gastrointestinal stromal tumors (GIST) treated with IM (imatinib). To date the therapeutic relevance of surgical resection of metastatic disease remains unknown except for the use in palliative intent. We analyzed overall survival (OS) and progression-free survival (PFS) in consecutive patients with metastatic GIST who underwent metastasectomy and received IM therapy (n = 239). Complete resection (R0+R1) was achieved in 177 patients. Median OS was 8.7 y for R0/R1 and 5.3 y in pts with R2 resection (p = 0.0001). In the group who were in remission at time of resection median OS was not reached in the R0/R1 surgery and 5.1 y in the R2-surgery (p = 0.0001). Median time to relapse/progression after resection of residual disease was not reached in the R0/R1 and 1.9 years in the R2 group of patients, who were resected in response. No difference in mPFS was seen in patients progressing at time of surgery. Our analysis implicates possible long-term survival in patients in whom surgical complete remission can be achieved. Incomplete resection, including debulking surgery does not seem to prolong survival. Despite the retrospective character and likely selection bias, this analysis may help in decision making for surgical approaches in metastatic GIST.

Long-term complete remission of metastatic breast cancer induced by a steroidal aromatase inhibitor after failure of a non-steroidal aromatase inhibitor

Patient: Female, 56Final Diagnosis: Breast cancerSymptoms: Solid mass in the right breastMedication: ExemestaneClinical Procedure: —Specialty: OncologyObjective:Unusual clinical courseBackground:The efficacy of third-generation aromatase inhibitors for hormone receptor-positive postmenopausal metastatic breast cancer is well established. Although several clinical trials have reported incomplete cross-resistance between different aromatase inhibitors, few cases of complete responses of recurrent metastatic breast cancer occurring after substituting a second aromatase inhibitor have been reported. We here present a rare case of non-steroidal aromatase inhibitor-tolerant metastatic breast cancer with long-term complete remission following substitution of a steroidal aromatase inhibitor.Case Report:We present the case of a 56-year-old Japanese woman who underwent right breast-conserving surgery for breast cancer, TNM staging T1, N0, M0, Stage I. She received adjuvant chemotherapy with 6 cycles of FEC100 and radiation therapy, and then began hormonal therapy with anastrozole. Twelve months postoperatively, computed tomography (CT) revealed multiple lung metastases. Exemestane was substituted for anastrozole. After 3 months of exemestane, CT showed that all lung metastases had completely resolved. Her complete response was maintained for 5 years: she died during a tsunami 6 years after the initial surgery.Conclusions:Substitution of a steroidal for a non-steroidal aromatase inhibitor produced a sustained complete remission in a patient with hormonal receptor-positive postmenopausal recurrent breast cancer.Achieving complete response after switching from a non-steroidal to a steroidal aromatase inhibitor in a hormonal receptor-positive postmenopausal recurrent breast cancer contributed to a higher quality of life for the patient. Further investigation is needed to identify the predictors of long-term remission following such a switch.

Long-term clinical and molecular remissions in patients with mantle cell lymphoma following high-dose therapy and autologous stem cell transplantation

Long-term clinical and molecular remissions in patients with mantle cell lymphoma (MCL) following high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) have been evaluated in only a few studies. Thirty-six patients with MCL received ASCT in our institution (27 patients undergoing first-line therapy, 8 patients undergoing second-line therapy, and 1 patient undergoing third-line therapy). In the case of long-term remission (≥5years; n = 8), peripheral blood was tested for minimal residual disease (MRD) by t(11; 14) polymerase chain reaction (PCR) and immunoglobulin heavy-chain (IGH) PCR at the last follow-up. Ten-year overall survival (OS), progression-free survival (PFS), and freedom from progression (FFP) after first-line ASCT were 42%, 43%, and 54%; after second-line ASCT, these were all 0%. Four-year OS, PFS, and FFP for the first-line cohort were 75%, 48%, and 61%, respectively. Four-year OS, PFS, and FFP after second-line ASCT were 55%, 30%, and 30%, respectively. Treatment-related mortality (3months after ASCT) was 0%. The only prognostic factor for OS, PFS, and FFP was treatment line (p = 0.011, p = 0.046, and p = 0.023, respectively). No relapses occurred after 5years following ASCT. So far, eight patients developed sustained long-term clinical and molecular complete remissions of up to 14.6years following ASCT in the first treatment line. Sustained long-term clinical and molecular remissions can be achieved following ASCT in the first treatment line and apparently less frequent in the second treatment line.

Helicobacter pylori and mucosa-associated lymphoid tissue: what's new

Low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach, gastric MALT lymphoma, is associated with Helicobacter pylori infection. The eradication of H pylori using antibiotics is successful in 60% to 80% of affected patients. In contrast to the previous paradigm, we and other investigators have shown that a certain proportion of patients with H pylori-positive early-stage diffuse large B-cell lymphoma (DLBCL) of the stomach with histological evidence of MALT lymphoma, including high-grade transformed gastric MALT lymphoma and gastric DLBCL(MALT), achieved long-term complete pathological remission (pCR) after first-line H pylori eradication therapy, indicating that the loss of H pylori dependence and high-grade transformation are separate events in the progression of gastric lymphoma. In addition, patients with H pylori-positive gastric DLBCL without histological evidence of MALT (gastric pure DLBCL) may also respond to H pylori eradication therapy. A long-term follow-up study showed that patients who achieved pCR remained lymphoma free. Gastric MALT lymphoma is indirectly influenced by H pylori infection through T-cell stimulation, and recent studies have shown that H pylori-triggering chemokines and their receptors, H pylori-associated epigenetic changes, H pylori-regulated miRNA expression, and tumor infiltration by CD4+CD25+ regulatory T cells contribute to lymphomagenesis of gastric MALT lymphoma. Recent studies have also demonstrated that the translocation of CagA into B lymphocytes inhibits apoptosis through p53 accumulation, BAD phosphorylation, and the up-regulation of Bcl-2 and Bcl-XL expression. In gastric MALT lymphoma, CagA may stimulate lymphomagenesis directly, through the regulation of signal transduction, and intracellular CagA is associated with H pylori dependence. These findings represent a substantial paradigm shift compared with the classical theory of H pylori-reactive T cells contributing indirectly to the development of MALT lymphoma. In conclusion, a wide range of H pylori-related gastric lymphomas have been identified. The use of antibiotics as the sole first-line therapy for early-stage gastric pure DLBCL requires validation in a prospective study. The clinical and biological significance of the CagA oncoprotein in the lymphomagenesis of gastric MALT lymphoma warrants further study.

Immunotherapeutic strategies for the treatment of renal cell carcinoma: where are we now?

Immunotherapy with cytokines was the first effective treatment in metastatic renal cell carcinoma (mRCC). Long-term responders and complete remissions were observed, but efficacy in the overall population was limited with the consequence that targeted agents replaced cytokines. The discovery of tumor associated antigens as direct targets paved the way from theses rather unspecific to specific immunotherapeutic strategies, which are discussed in this review. Autologous or dendritic cell (DC) based tumor vaccination with vitespen or AGS-003, adoptive T-cell transfer and synthetic peptide vaccination with IMA901 are new and promising approaches. Besides that the more passive strategies of antibody dependent cytotoxicity with the VEGF antibody bevacizumab or the carbonic anhydrase IX antibody girentuximab are discussed. Immunomodulation by cyclophosphamide, tyrosine kinase inhibitors or nivolumab, which targets the PD-1 axis, further promote T-cell activation and combinatory strategies with these agents are outlined.

Long-term Efficacy and Safety of Endoscopic Resection for Patients With Mucosal Adenocarcinoma of the Esophagus

Barrett's esophagus-associated high-grade dysplasia is commonly treated by endoscopy. However, most guidelines offer no recommendations for endoscopic treatment of mucosal adenocarcinoma of the esophagus (mAC). We investigated the efficacy and safety of endoscopic resection in a large series of patients with mAC. We collected data from 1000 consecutive patients (mean age, 69.1 ± 10.7 years; 861 men) with mAC (481 with short-segment and 519 with long-segment Barrett's esophagus) who presented at a tertiary care center from October 1996 to September 2010. Patients with low-grade and high-grade dysplasia and submucosal or more advanced cancer were excluded. All patients underwent endoscopic resection of mACs. Patients found to have submucosal cancer at their first endoscopy examination were excluded from the analysis. After a mean follow-up period of 56.6 ± 33.4 months, 963 patients (96.3%) had achieved a complete response; surgery was necessary in 12 patients (3.7%) after endoscopic therapy failed. Metachronous lesions or recurrence of cancer developed during the follow-up period in 140 patients (14.5%) but endoscopic re-treatment was successful in 115, resulting in a long-term complete remission rate of 93.8%; 111 died of concomitant disease and 2 of Barrett's esophagus-associated cancer. The calculated 10-year survival rate of patients who underwent endoscopic resection of mACs was 75%. Major complications developed in 15 patients (1.5%) but could be managed conservatively. Endoscopic therapy is highly effective and safe for patients with mAC, with excellent long-term results. In an almost 5-year follow-up of 1000 patients treated with endoscopic resection, there was no mortality and less than 2% had major complications. Endoscopic therapy should become the standard of care for patients with mAC.